Novel compounds

ABSTRACT

The present invention relates to new CGRP-antagonists of general formulae Ia and Ib 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3 , R 4  and R 5  are defined as mentioned below, the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates, the mixtures and the salts thereof as well as the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, pharmaceutical compositions containing these compounds, the use thereof and processes for the preparation thereof.

The present invention relates to new CGRP-antagonists of generalformulae Ia and Ib

wherein R¹, R², R³, R⁴ and R⁵ are defined as mentioned below, thetautomers, the isomers, the diastereomers, the enantiomers, thehydrates, the mixtures and the salts thereof as well as the hydrates ofthe salts, particularly the physiologically acceptable salts thereofwith inorganic or organic acids or bases, pharmaceutical compositionscontaining these compounds, the use thereof and processes for thepreparation thereof.

DETAILED DESCRIPTION OF THE INVENTION

In the above general formulae Ia and Ib in a first embodiment

-   R¹ denotes a group of general formula II

wherein

-   G-L denotes N, N—C(R^(1.1))₂, C═C(R^(1.1)), C═N, C(R^(1.1)),    C(R^(1.1))—C(R^(1.1))₂, C(R^(1.1))—C(R^(1.1))₂—C(R^(1.1))₂,    C═C(R^(1.1))—C(R^(1.1))₂, C(R^(1.1))—C(R^(1.1))═C(R^(1.1)),    C(R^(1.1))—C(R^(1.1))₂—N(R^(1.2)), C═C(R^(1.1))—N(R^(1.2)),    C(R^(1.1))—C(R^(1.1))═N, C(R^(1.1))—N(R^(1.2))—C(R^(1.1))₂,    C═N—C(R^(1.1))₂, C(R^(1.1))—N═C(R^(1.1)),    C(R^(1.1))—N(R^(1.2))—N(R^(1.2)), C═N—N(R^(1.2)),    N—C(R^(1.1))₂—C(R^(1.1))₂, N—C(R^(1.1))═C(R^(1.1)),    N—C(R^(1.1))₂—N(R^(1.2)), N—C(R^(1.1))═N, N—N(R^(1.2))—C(R^(1.1))₂    or N—N═C(R^(1.1)),-   Q-T denotes C(R^(1.3))₂—C(R^(1.3))₂, C(R^(1.3))═C(R^(1.3)),    N═C(R^(1.3)), C(R^(1.3))₂—C(═O), C(═O)—C(R^(1.3))₂,    C(R^(1.3))₂—S(O), or C(R^(1.3))₂—N(R^(1.3)),    -   while a group C(R^(1.3))₂ contained in Q-T may also denote a        cyclic group which is selected from among C₃₋₆-cycloalkyl,        C₅₋₆-cycloalkenyl or heterocyclyl, or    -   in a group C(R^(1.3))₂—C(R^(1.3))₂, C(R^(1.3))═C(R^(1.3)) or        C(R^(1.3))₂—N(R^(1.3)) contained in Q-T in each case a group        R^(1.3) together with an adjacent group R^(1.3) and the atoms to        which these groups are bound may also denote a C₃₋₆-cycloalkyl,        C₅₋₆-cycloalkenyl, heterocyclyl, aryl or heteroaryl group, which        may be substituted independently of one another by 1, 2 or 3        substituents R^(1.3.1),-   R^(1.1) denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, —CN, —OH, —O—C₁₋₃-alkyl,    -   (c) a C₁₋₃-alkyl- or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(1.2) denotes H or C₁₋₆-alkyl,-   R^(1.3) independently of one another denote    -   (a) H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₆-cycloalkyl,    -   (b) an aryl group optionally substituted by 1, 2 or 3        substituents R^(1.3.2), wherein the substituents R^(1.3.2) may        be identical or different,    -   (c) a heteroaryl group optionally substituted by 1, 2 or 3        substituents R^(1.3.2), wherein the substituents R^(1.3.2) may        be identical or different,    -   (d) a heterocyclic group optionally substituted by 1, 2 or 3        substituents R^(1.3.2), wherein the substituents R^(1.3.2) may        be identical or different,-   R^(1.3.1) denotes    -   (a) H, halogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   (b) —O—R^(1.3.1.1), —O—C₁₋₆-alkylene-NR^(1.3.1.2)R^(1.3.1.3),        —O—(CH₂)_(s)—O—R^(1.3.1.1), —CO₂—R^(1.3.1.1),        —C(O)—NR^(1.3.1.2)R^(1.3.1.3), —O—C(O)—NR^(1.3.1.2)R^(1.3.1.3),        —NR^(1.3.1.1)—C(O)—NR^(1.3.1.2)R^(1.3.1.3),        —NR^(1.3.1,2)—C(O)—R^(1.3.1.3),        —NR^(1.3.1,2)—C(O)—O—R^(1.3.1.3), —SO₂—NR^(1.3.1.2)R^(1.3.1.3),        —NR^(1.3.1,2)—SO₂—R^(1.3.1.3), —S(O)_(m)—R^(1.3.1.2), —CN,        —NR^(1.3.1.2)R^(1.3.1.3),        —NR^(1.3.1.1)—C(O)—NR^(1.3.1.2)R^(1.3.1.3), —O—C(O)—R^(1.3.1.1),    -   (c) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,    -   (d) an aryl group substituted by 1, 2 or 3 substituents        R^(1.3.1.1), wherein the substituents R^(1.3.1.1) may be        identical or different,    -   (e) a heteroaryl group substituted by 1, 2 or 3 substituents        R^(1.3.1.1), wherein the substituents R^(1.3.1.1) may be        identical or different,    -   (f) a heterocyclic group substituted by 1, 2 or 3 substituents        R^(1.3.1.1), wherein the substituents R^(1.3.1.1) may be        identical or different,-   R^(1.3.2) denotes    -   (a) halogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   (b) —O—R^(1.3.2.1), —O—(CH₂)_(s)—O—R^(1.3.2.1), —CO₂R^(1.3.2.1),        —C(O)—NR^(1.3.2.2)R^(1.3.2.3), —O—(CO)—NR^(1.3.2.2)R^(1.3.2.3),        —N(R^(1.3.2.1))—C(O)—NR^(1.3.2.2)R^(1.3.2.3),        —N(R^(1.3.2.2))—C(O)—R^(1.3.2.3),        —N(R^(1.3.2.2))—C(O)—O—R^(1.3.2.3),        —SO₂—NR^(1.3.2.2)R^(1.3.2.3), —N(R^(1.3.2.2))—SO₂—R^(1.3.2.3),        —S(O)_(m)—R^(1.3.2.2), —CN, —NR^(1.3.2.2)R^(1.3.2.3),        —N(R^(1.3.2.1))—C(O)—NR^(1.3.2.2)R^(1.3.2.3),        —O—C(O)—R^(1.3.2.1) or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(1.3.1.1) denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, benzyl which        may be substituted by a group R^(1.3.1.1.1), or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(1.3.1.1.1) denotes halogen, HO— or C₁₋₆-alkyl-O—,-   R^(1.3.1.2) denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl or benzyl,        wherein the groups may be unsubstituted or substituted by        halogen, HO— or C₁₋₆-alkyl-O—, or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(1.3.1.3) denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl or benzyl,        wherein the groups may be unsubstituted or substituted by        halogen, HO— or C₁₋₆-alkyl-O—, or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms, or-   R^(1.3.1.2) and R^(1.3.1.3) together may also form a ring which is    selected from among azetidinyl, pyrrolidinyl, piperidinyl,    piperazinyl and morpholinyl, wherein the ring may be unsubstituted    or substituted by 1, 2 or 3 substituents R^(1.3.1.1) or fluorine,    wherein the substituents R^(1.3.1.1) are independent of one another,-   R^(1.3.2.1) denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, benzyl which        may be substituted by a group R^(1.3.2.1.1), or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(1.3.2.1.1) denotes halogen, HO— or C₁₋₆-alkyl-O—,-   R^(1.3.2.2) denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl or benzyl,        wherein the groups may be unsubstituted or substituted by        halogen, HO— or C₁₋₆-alkyl-O—, or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(1.3.2.3) denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl or benzyl,        wherein the groups may be unsubstituted or substituted by        halogen, HO— or C₁₋₆-alkyl-O—, or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms, or-   R^(1.3.2.2) and R^(1.3.2.3) together may also form a ring which is    selected from among azetidinyl, pyrrolidinyl, piperidinyl,    piperazinyl and morpholinyl, wherein the ring may be unsubstituted    or substituted by 1, 2 or 3 substituents R^(1.3.2.1) or fluorine,    wherein the substituents R^(1.3.2.1) are independent of one another,-   m denotes one of the numbers 0, 1 or 2,-   s denotes one of the numbers 1, 2 or 3,-   R² denotes    -   (a) H,    -   (b) F, —CN, C₁₋₃-alkyl, —CO₂—R^(2.1) or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(2.1) denotes H or C₁₋₆-alkyl,-   R³ denotes    -   (a) H,    -   (b) C₁₋₆-alkylene-R^(3.1),    -   (c) a C₃₋₆-cycloalkyl group substituted by one or two groups        R^(3.2),    -   (d) a C₅₋₇-cycloalkenyl group substituted by one or two groups        R^(3.2),    -   (e) an aryl group substituted by one or two groups R^(3.2),    -   (f) a heterocyclyl group substituted by one or two groups        R^(3.2),    -   (g) a C₅₋₇-cycloalkyl group which may be fused to an aryl or        heteroaryl group and is additionally substituted by one or two        groups R^(3.2),    -   (h) a heteroaryl group substituted by one or two groups R^(3.2),    -   (i) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(3.1) denotes    -   (a) H,    -   (b) an aryl group substituted by the groups R^(3.1.1) and        R^(3.1.2),    -   (c) a heteroaryl group substituted by the groups R^(3.1.1) and        R^(3.1.2),-   R^(3.1.1) denotes    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —CN, —O—C₁₋₃-alkyl,        —O—C(O)—C₁₋₃-alkyl, —NR^(3.1.1.1)R^(3.1.1.2), —S(O),        —C₁₋₃-alkyl, —NR^(3.1.1.1)—C(O)—C₁₋₃-alkyl,        —C(O)—NR^(3.1.1.1)R^(3.1.12), —C(O)—O—R^(3.1.1.3),        —NR^(3.1.1.1)—C(O)—O—C₁₋₃-alkyl, —O—C(O)—NR^(3.1.1.1)R^(3.1.12),    -   (c) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(3.1.1.1) denotes H, C₁₋₃-alkyl and-   R^(3.1.1.2) denotes H, C₁₋₃-alkyl, or-   R^(3.1.1.1) and R^(3.1.1.2) together with the nitrogen atom to which    they are bound also denote a group which is selected from    morpholinyl, thiomorpholinyl, piperidinyl, piperidonyl, piperazinyl,    pyrrolidinyl and azetidinyl, while the group may additionally be    substituted by one or two substituents selected from F, —OH,    —O—C₁₋₃-alkyl, —OCF₃, C₁₋₃-alkyl and CF₃,-   R^(3.1.1.3) denotes H, C₁₋₃-alkyl,-   R^(3.1.2) denotes    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —CN, —O—C₁₋₃-alkyl,    -   (c) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms, or-   R^(3.2) independently of one another denote    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —CN, —O—C₁₋₃-alkyl,        —O—C(O)—C₁₋₃-alkyl, —NR^(3.2.1)R^(3.2.2), —S(O)_(m)—C₁₋₃-alkyl,        —NR^(3.2.1)—C(O)—C₁₋₃-alkyl, —C(O)—NR^(3.2.1)R^(3.2.2),        —C(O)—O—R^(3.2.3), —NR^(3.2.1)—C(O)—O—C₁₋₃-alkyl,        —O—C(O)—NR^(3.2.1)R^(3.2.2),    -   (c) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(3.2.1) denotes H, C₁₋₃-alkyl and-   R^(3.2.2) denotes H, C₁₋₃-alkyl, or-   R^(3.2.1) and R^(3.2.2) together with the nitrogen atom to which    they are bound also denote a group which is selected from    morpholinyl, thiomorpholinyl, piperidinyl, piperidonyl, piperazinyl,    pyrrolidinyl and azetidinyl, while the group may additionally be    substituted by one or two substituents selected from F, —OH,    —O—C₁₋₃-alkyl, —OCF₃, C₁₋₃-alkyl and CF₃,-   R^(3.2.3) denotes H, C₁₋₃-alkyl,-   R⁴ denotes    -   (a) H,    -   (b) C₁₋₆-alkylene-R^(4.1),    -   (c) a C₃₋₆-cycloalkyl group substituted by one or two groups        R^(4.2),    -   (d) a C₆₋₇-cycloalkenyl group substituted by one or two groups        R^(4.2),    -   (e) an aryl group substituted by one or two groups R^(4.2),    -   (f) a heterocyclyl group substituted by one or two groups        R^(4.2),    -   (g) a C₆₋₇-cycloalkyl group which may be fused to an aryl or        heteroaryl group, while the resultant bicyclic group is        additionally substituted by one or two groups R^(4.2),    -   (h) a heteroaryl group substituted by one or two groups R^(4.2),    -   (i) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(4.1) denotes    -   (a) H,    -   (b) an aryl group substituted by the groups R^(4.1.1) and        R^(4.1.2),    -   (c) a heteroaryl group substituted by the groups R^(4.1.1) and        R^(4.1.2),-   R^(4.1.1) denotes    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —CN, —O—C₁₋₃-alkyl,        —O—C(O)—C₁₋₃-alkyl, —NR^(4.1.1.1)R^(4.1.1.2),        —S(O)_(m)—C₁₋₃-alkyl, —NR^(4.1.1.1)—C(O)—C₁₋₃-alkyl,        —C(O)—NR^(4.1.1.1)R^(4.1.1.2), —C(O)—O—R^(4.1.1.3),        —NR^(4.1.1.1)—C(O)—O—C₁₋₃-alkyl,        —O—C(O)—NR^(4.1.1.1)R^(4.1.1.2),    -   (c) a C₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(4.1.1.1) denotes H, C₁₋₃-alkyl and-   R^(4.1.1.2) denotes H, C₁₋₃-alkyl, or-   R^(4.1.1.1) and R^(4.1.1.2) together with the nitrogen atom to which    they are bound also denote a group which is selected from    morpholinyl, thiomorpholinyl, piperidinyl, piperidonyl, piperazinyl,    pyrrolidinyl and azetidinyl, while the group may additionally be    substituted by one or two substituents selected from F, —OH,    —O—C₁₋₃-alkyl, —OCF₃, C₁₋₃-alkyl and CF₃,-   R^(4.1.1.3) denotes H, C₁₋₃-alkyl,-   R^(4.1.2) denotes    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —CN, —O—C₁₋₃-alkyl,    -   (c) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms, or-   R^(4.2) independently of one another denote    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —CN, —O—C₁₋₃-alkyl,        —O—C(O)—C₁₋₃-alkyl, —NR^(4.2.1)R^(4.2.2), —S(O)_(m)—C₁₋₃-alkyl,        —NR^(4.2.1)—C(O)—C₁₋₃-alkyl, —C(O)—NR^(4.2.1)R^(4.2.2),        —C(O)—O—R^(4.2.3), —NR^(4.2.1)—C(O)—O—C₁₋₃-alkyl,        —O—C(O)—NR^(4.2.1)R^(4.2.2),    -   (c) a C₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(4.2.1) denotes H, C₁₋₃-alkyl and-   R^(4.2.2.) denotes H, C₁₋₃-alkyl, or-   R^(4.2.1) and R^(4.2.2) together with the nitrogen atom to which    they are bound also denote a group which is selected from    morpholinyl, thiomorpholinyl, piperidinyl, piperidonyl, piperazinyl,    pyrrolidinyl and azetidinyl, while the group may additionally be    substituted by one or two substituents selected from F, —OH,    —O—C₁₋₃-alkyl, —OCF₃, C₁₋₃-alkyl and CF₃,-   R^(4.2.3) denotes H, C₁₋₃-alkyl,-   R³ and R⁴ together with the nitrogen atom to which they are bound    denote:    -   (a) a saturated 5-, 6- or 7-membered heterocyclic group which is        substituted at a carbon atom by a group R^(4.3) or by two groups        R^(4.3) and R^(4.4),    -   (b) a saturated 5-, 6- or 7-membered heterocyclic group which is        substituted at two adjacent carbon atoms by in each case a group        R^(4.3) and R^(4.4),    -   (c) a saturated 5-, 6- or 7-membered heterocyclic group which is        substituted at a carbon atom by a group R^(4.3) or by two groups        R^(4.3) and R^(4.4) and is additionally fused to a 5-, 6- or        7-membered cycloalkyl or heterocyclyl group, while the fused-on        cycloalkyl or heterocyclyl group is substituted by 1, 2 or 3        groups R^(4.5),    -   (d) a monounsaturated 5-, 6- or 7-membered heterocyclic group        which is substituted at a carbon atom by a group R^(4.3) or by        two groups R^(4.3) and R^(4.4) and is additionally fused to a        phenyl group, while the fused-on phenyl group is substituted by        1, 2 or 3 groups R^(4.5),    -   (e) a monounsaturated 5-, 6- or 7-membered heterocyclic group        which is substituted at a carbon atom by a group R^(4.3) or by        two groups R^(4.3) and R^(4.4) and is additionally fused to a 5-        or 6-membered heteroaryl group, while the fused-on heteroaryl        group is substituted by 1, 2 or 3 groups R^(4.5), or    -   (f) a heteroaryl group which is substituted at 1, 2 or 3 carbon        atoms by in each case a group R^(4.5),-   R^(4.3) independently of one another denote    -   (a) H, C₁₋₃-alkyl, C₂₋₆-alkynyl, aryl, —C₁₋₃-alkylene-R^(4.3.1),        C₁₋₃-alkyl-O—C(O)—, HO—C(O)—, F, —O—C₁₋₃-alkyl, —OH, —CN,    -   (b) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(4.3.1) denotes H, C₁₋₃-alkyl-O—C(O)—, —NH₂, (C₁₋₄-alkyl)-NH,    (C₁₋₄-alkyl)₂N, C₃₋₆-cycloalkyl, heterocyclyl, heteroaryl, aryl,-   R^(4.4) denotes    -   (a) H, C₁₋₃-alkyl-, —OH, —O—C₁₋₃-alkyl or    -   (b) a C₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(4.3) and R^(4.4) together with the carbon atoms to which they are    bound also denote a C₃₋₆-cycloalkyl-, C₅₋₆-cycloalkenyl- or    heterocyclyl group,-   R^(4.5) independently of one another denote    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl,        —S(O)_(m)—C₁₋₃-alkyl, —NR^(4.5.2)R^(4.5.3), —CN,        —C(O)—O—R^(4.5.1), —C(O)—NR^(4.5.2)R^(4.5.3),    -   (c) a C₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,    -   (d) aryl, heteroaryl,-   R^(4.5.1) denotes H,-   R^(4.5.2) denotes H,-   R^(4.5.3) denotes H, C₁₋₃-alkyl, or-   R^(4.5.2) and R^(4.5.3) together with the nitrogen atom to which    they are bound also denote a group which is selected from    morpholinyl, thiomorpholinyl, piperidinyl, piperidonyl, piperazinyl,    pyrrolidinyl and azetidinyl, while the group may additionally be    substituted by one or two substituents selected from F, —OH, —OCF₃,    C₁₋₃-alkyl and CF₃,-   R⁵ denotes H, —CH₂—R^(5.1) or benzyl, and-   R^(5.1) denotes a C₁₋₃-alkyl group wherein each methylene group is    substituted by up to two fluorine atoms and each methyl group is    substituted by up to three fluorine atoms,    the tautomers, the diastereomers, the enantiomers, the hydrates, the    mixtures thereof and the salts thereof as well as the hydrates of    the salts, particularly the physiologically acceptable salts thereof    with inorganic or organic acids or bases.

A second embodiment of the present invention comprises the compounds ofthe above general formulae Ia and Ib, wherein R², R³, R⁴ and R⁵ aredefined as hereinbefore in the first embodiment and

-   R¹ denotes a group of general formula II

wherein

-   G-L denotes N, N—C(R^(1.1))₂, C═C(R^(1.1)), C═N, C(R^(1.1)),    C(R^(1.1))—C(R^(1.1))₂, C(R^(1.1))—C(R^(1.1))₂—C(R^(1.1))₂,    C═C(R^(1.1))—C(R^(1.1))₂, C(R^(1.1))—C(R^(1.1))═C(R^(1.1)),    C(R^(1.1))—C(R^(1.1))₂—N(R^(1.2)), C═C(R^(1.1))—N(R^(1.2)),    C(R^(1.1))—C(R^(1.1))═N, C(R^(1.1))—N(R^(1.2))—C(R^(1.1))₂,    C═N—C(R^(1.1))₂, C(R^(1.1))—N═C(R^(1.1)),    C(R^(1.1))—N(R^(1.2))—N(R^(1.2)), C═N—N(R^(1.3)),    N—C(R^(1.1))₂—C(R^(1.1))₂, N—C(R^(1.1))═C(R^(1.1)),    N—C(R^(1.1))₂—N(R^(1.2)), N—C(R^(1.1))═N, N—N(R^(1.2))—C(R^(1.1))₂    or N—N═C(R^(1.1)),-   Q-T denotes C(R^(1.3))₂—C(R^(1.3))₂, C(R^(1.3))═C(R^(1.3)),    N═C(R^(1.3)), C(R^(1.3))₂—C(═O), C(═O)—C(R^(1.3))₂,    C(R^(1.3))₂—S(O)_(m) or C(R^(1.3))₂—N(R^(1.3)),    -   while a group C(R^(1.3))₂ contained in Q-T may also denote a        cyclic group which is selected from among cyclobutyl,        cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, dioxanyl,        morpholinyl, thiomorpholinyl, thiomorpholinyl-S-oxide,        thiomorpholinyl-S-dioxide, azetidinyl, pyrrolidinyl,        piperidinyl, tetrahydrofuranyl, tetrahydropyranyl and        piperazinyl, or    -   in a group C(R^(1.3))₂—C(R^(1.3))₂, C(R^(1.3))═C(R^(1.3)) or        C(R^(1.3))₂—N(R^(1.3)) contained in Q-T in each case a group        R^(1.3) together with an adjacent group R^(1.3) and the atoms to        which these groups are bound may also denote a group selected        from cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl,        cyclohexenyl, dioxanyl, phenyl, naphthyl, thienyl, thiazolyl,        thiazolinyl, oxazolyl, oxazolinyl, imidazolyl, imidazolinyl,        imidazolidinyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,        pyrrolyl, pyrrolinyl, quinolinyl, isoquinolinyl, morpholinyl,        thiomorpholinyl, thiomorpholinyl-S-oxide,        thiomorpholinyl-S-dioxide, 1H-quinolinyl-2-one, azetidinyl,        pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl,        tetrahydropyridyl, furanyl, dihydrofuranyl, dihydropyranyl and        piperazinyl, which may be substituted independently of one        another denote by 1, 2 or 3 substituents R^(1.3.1),-   R^(1.1) denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, —CN, —OH, —O—C₁₋₃-alkyl,    -   (c) a C₁₋₃-alkyl- or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(1.2) denotes H or C₁₋₆-alkyl,-   R^(1.3) independently of one another denote    -   (a) H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₆-cycloalkyl,    -   (b) an aryl group optionally substituted by 1, 2 or 3        substituents R^(1.3.2), wherein the substituents R^(1.3.2) may        be identical or different,    -   (c) a heteroaryl group optionally substituted by 1, 2 or 3        substituents R^(1.3.2), wherein the substituents R^(1.3.2) may        be identical or different,    -   (d) a heterocyclic group optionally substituted by 1, 2 or 3        substituents R^(1.3.2), wherein the substituents R^(1.3.2) may        be identical or different,-   R^(1.3.1) denotes    -   (a) H, halogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   (b) —O—R^(1.3.1.1), —O—C₁₋₆-alkylene-NR^(1.3.1.2)R^(1.3.1.3),        —O—(CH₂)_(s)—O—R^(1.3.1.1), —CO₂—R^(1.3.1.1),        C(O)—NR^(1.3.1.2)R^(1.3.1.3), —O—C(O)—NR^(1.3.1.2)R^(1.3.1.3),        —NR^(1.3.1.1)—C(O)—NR^(1.3.1.2)R^(1.3.1.3),        —NR^(1.3.1,2)—C(O)—R^(1.3.1.3),        —NR^(1.3.1,2)—C(O)—O—R^(1.3.1.3), —SO₂—NR^(1.3.1.2)R^(1.3.1.3),        —NR^(1.3.1,2)—SO₂—R^(1.3.1.3), —S(O)_(m)—R^(1.3.1.2), —CN,        —NR^(1.3.1.2)R^(1.3.1.3),        —NR^(1.3.1.1)—C(O)—NR^(1.3.1.2)R^(1.3.1.3), —O—C(O)—R^(1.3.1.1),    -   (c) a C₁₋₃-alkyl- or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,    -   (d) an aryl group substituted by 1, 2 or 3 substituents        R^(1.3.1.1), wherein the substituents R^(1.3.1.1) may be        identical or different,    -   (e) a heteroaryl group substituted by 1, 2 or 3 substituents        R^(1.3.1.1), wherein the substituents R^(1.3.1.1) may be        identical or different,    -   (f) a heterocyclic group substituted by 1, 2 or 3 substituents        R^(1.3.1.1), wherein the substituents R^(1.3.1.1.) may be        identical or different,-   R^(1.3.2) denotes    -   (a) halogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   (b) —O—R^(1.3.2.1), —O—(CH₂)_(s)—O—R^(1.3.2.1), —CO₂R^(1.3.2.1),        —C(O)—NR^(1.3.2.2)R^(1.3.2.3), —O—(CO)—NR^(1.3.2.2)R^(1.3.2.3),        —N(R^(1.3.2.1))—C(O)—NR^(1.3.2.2)R^(1.3.2.3),        —N(R^(1.3.2.2))—C(O)—R^(1.3.2.3),        —N(R^(1.3.2.2))—C(O)—O—R^(1.3.2.3),        —SO₂—NR^(1.3.2.2)R^(1.3.2.3), —N(R^(1.3.2.2))—SO₂—R^(1.3.2.3),        —S(O)_(m)—R^(1.3.2.2), —CN, —NR^(1.3.2.2)R^(1.3.2.3),        —N(R^(1.3.2.1))—C(O)—NR^(1.3.2.2)R^(1.3.2.3),        —O—C(O)—R^(1.3.2.1) or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(1.3.1.1) denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, benzyl which        may be substituted by a group R^(1.3.1.1.1), or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(1.3.1.1.1) denotes halogen, HO— or C₁₋₆-alkyl-O—,-   R^(1.3.1.2) denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl or benzyl,        wherein the groups may be unsubstituted or substituted by        halogen, HO— or C₁₋₆-alkyl-O—, or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(1.3.1.3) denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl or benzyl,        wherein the groups may be unsubstituted or substituted by        halogen, HO— or C₁₋₆-alkyl-O—, or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms, or-   R^(1.3.1.2) and R^(1.3.1.3) together may also form a ring which is    selected from among azetidinyl, pyrrolidinyl, piperidinyl,    piperazinyl and morpholinyl, wherein the ring may be unsubstituted    or substituted by 1, 2 or 3 substituents R^(1.3.1.1) or fluorine,    wherein the substituents R^(1.3.1.1) are independent of one another,-   R^(1.3.2.1) denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, benzyl which        may be substituted by a group R^(1.3.2.1.1), or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(1.3.2.1.1) denotes halogen, HO— or C₁₋₆-alkyl-O—,-   R^(1.3.2.2) denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl or benzyl,        wherein the groups may be unsubstituted or substituted by        halogen, HO— or C₁₋₆-alkyl-O—, or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(1.3.2.3) denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl or benzyl,        wherein the groups may be unsubstituted or substituted by        halogen, HO— or C₁₋₆-alkyl-O—, or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms, or-   R^(1.3.2.2) and R^(1.3.2.3) together may also form a ring which is    selected from among azetidinyl, pyrrolidinyl, piperidinyl,    piperazinyl and morpholinyl, wherein the ring may be unsubstituted    or substituted by 1, 2 or 3 substituents R^(1.3.2.1) or fluorine,    wherein the substituents R^(1.3.2.1) are independent of one another,-   m denotes one of the numbers 0, 1 or 2 and-   s denotes one of the numbers 1, 2 or 3,    the tautomers, the diastereomers, the enantiomers, the hydrates, the    mixtures thereof and the salts thereof as well as the hydrates of    the salts, particularly the physiologically acceptable salts thereof    with inorganic or organic acids or bases.

A third embodiment of the present invention comprises the compounds ofthe above general formulae Ia and Ib, wherein R², R³, R⁴ and R⁵ aredefined as hereinbefore in the first embodiment and

-   R¹ denotes a group of general formulae

wherein

-   Q-T denotes C(R^(1.3))₂—C(R^(1.3))₂, C(R^(1.3))═C(R^(1.3)),    N═C(R^(1.3)), C(R^(1.3))₂—C(═O), C(═O)—C(R^(1.3))₂,    C(R^(1.3))₂—S(O)_(m) or C(R^(1.3))₂—N(R^(1.3)),    -   while in a group C(R^(1.3))₂—C(R^(1.3))₂, C(R^(1.3))═C(R^(1.3))        or C(R^(1.3))₂—N(R^(1.3)) contained in Q-T in each case a group        R^(1.3) together with an adjacent group R^(1.3) and the atoms to        which these groups are bound may also denote a group selected        from cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl,        cyclohexenyl, dioxanyl, phenyl, naphthyl, thienyl, thiazolyl,        thiazolinyl, oxazolyl, oxazolinyl, imidazolyl, imidazolinyl,        imidazolidinyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,        pyrrolyl, pyrrolinyl, quinolinyl, isoquinolinyl, morpholinyl,        thiomorpholinyl, thiomorpholinyl-S-oxide,        thiomorpholinyl-S-dioxide, azetidinyl, pyrrolidinyl,        piperidinyl, tetrahydrofuranyl, tetrahydropyranyl,        tetrahydropyridyl, furanyl, dihydrofuranyl, dihydropyranyl and        piperazinyl, which may be substituted independently of one        another denote by 1, 2 or 3 substituents R^(1.3.1,)-   R^(1.1) denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, —CN, —OH, —O—C₁₋₃-alkyl,    -   (c) a C₁₋₃-alkyl- or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(1.3) independently of one another denote    -   (a) H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₆-cycloalkyl,    -   (b) an aryl group optionally substituted by 1, 2 or 3        substituents R^(1.3.2), wherein the substituents R^(1.3.2) may        be identical or different,    -   (c) a heteroaryl group optionally substituted by 1, 2 or 3        substituents R^(1.3.2.), wherein the substituents R^(1.3.2) may        be identical or different,    -   (d) a heterocyclic group optionally substituted by 1, 2 or 3        substituents R^(1.3.2), wherein the substituents R^(1.3.2) may        be identical or different,-   R^(1.3.1) denotes    -   (a) H, halogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   (b) —O—R^(1.3.1.1), —O—C₁₋₆-alkylene-NR^(1.3.1.2)R^(1.3.1.3),        —CO₂R^(1.3.1.1), —C(O)NR^(1.3.1.2)R^(1.3.1.3),        —SO₂—NR^(1.3.1.2)R^(1.3.1.3), —N(R^(1.3.1.2))—SO₂—R^(1.3.1.3),        —S(O)_(m)R^(1.3.1.2), —CN, —NR^(1.3.1.2)R^(1.3.1.3),        —O—C(O)—R^(1.3.1.1) or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(1.3.2) denotes    -   (a) halogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   (b) —O—R^(1.3.2.1), —O—(CH₂)_(s)—O—R^(1.3.2.1), —CO₂R^(1.3.2.1),        —S(O)_(m)—R^(1.3.2.2), —CN, —O—C(O)—R^(1.3.2.1) or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(1.3.1.1) denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, benzyl which        may be substituted by a group R^(1.3.1.1.1), or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(1.3.1.1.1) denotes halogen, HO— or C₁₋₆-alkyl-O—,-   R^(1.3.1.2) denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, or benzyl,        wherein the groups may be unsubstituted or substituted by        halogen, HO— or C₁₋₆-alkyl-O—, or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(1.3.1.3) denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, or benzyl,        wherein the groups may be unsubstituted or substituted by        halogen, HO— or C₁₋₆-alkyl-O—, or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms, or-   R^(1.3.1.2) and R^(1.3.1.3) together may also form a ring which is    selected from among azetidinyl, pyrrolidinyl, piperidinyl,    piperazinyl and morpholinyl, wherein the ring may be unsubstituted    or substituted by 1, 2 or 3 substituents R^(1.3.1.1), wherein the    substituents R^(1.3.1.1) are independent of one another,-   R^(1.3.2.1) denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, benzyl which        may be substituted by a group R^(1.3.2.1.1), or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(1.3.2.1.1) denotes halogen, HO— or C₁₋₆-alkyl-O—,-   R^(1.3.2.2) denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, or benzyl,        wherein the groups may be unsubstituted or substituted by        halogen, HO— or C₁₋₆-alkyl-O—, or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(1.3.2.3) denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, or benzyl,        wherein the groups may be unsubstituted or substituted by        halogen, HO— or C₁₋₆-alkyl-O—, or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms, or-   R^(1.3.2.2) and R^(1.3.2.3) together may also form a ring which is    selected from among azetidinyl, pyrrolidinyl, piperidinyl,    piperazinyl and morpholinyl, wherein the ring may be unsubstituted    or substituted by 1, 2 or 3 substituents R^(1.3.2.1), wherein the    substituents R^(1.3.2.1) are independent of one another,-   m denotes one of the numbers 0, 1 or 2 and-   s denotes one of the numbers 1, 2 or 3,    the tautomers, the diastereomers, the enantiomers, the hydrates, the    mixtures thereof and the salts thereof as well as the hydrates of    the salts, particularly the physiologically acceptable salts thereof    with inorganic or organic acids or bases.

A fourth embodiment of the present invention comprises the compounds ofthe above general formulae Ia and Ib, wherein R², R³, R⁴ and R⁵ aredefined as hereinbefore in the first embodiment and

-   R¹ denotes a group of general formulae

wherein

-   Q-T denotes C(R^(1.3))₂—C(R^(1.3))₂, C(R^(1.3))═C(R^(1.3)),    N═C(R^(1.3)), C(R^(1.3))₂—C(═O), C(═O)—C(R^(1.3))₂,    C(R^(1.3))₂—S(O)_(m) or C(R^(1.3))₂—N(R^(1.3)),    -   while in a group C(R^(1.3))₂—C(R^(1.3))₂, C(R^(1.3))═C(R^(1.3))        or C(R^(1.3))₂—N(R^(1.3)) contained in Q-T in each case a group        R^(1.3) together with an adjacent group R^(1.3) and the atoms to        which these groups are bound may also denote a group selected        from cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl,        dioxanyl, phenyl, naphthyl, thienyl, pyridyl, pyrazinyl,        pyridazinyl, quinolinyl, isoquinolinyl, morpholinyl,        pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl        and piperazinyl, which may be substituted independently of one        another denote by 1, 2 or 3 substituents R^(1.3.1),-   R^(1.1) denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, —CN, —OH, —O—C₁₋₃-alkyl,    -   (c) a C₁₋₃-alkyl- or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(1.3) denotes    -   (a) H, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   (b) an aryl group optionally substituted by 1, 2 or 3        substituents R^(1.3.2), wherein the substituents R^(1.3.2) may        be identical or different,    -   (c) a heteroaryl group optionally substituted by 1, 2 or 3        substituents R^(1.3.2), wherein the substituents R^(1.3.2) may        be identical or different,    -   (d) a heterocyclic group optionally substituted by 1, 2 or 3        substituents R^(1.3.2), wherein the substituents R^(1.3.2) may        be identical or different,-   R^(1.3.1) denotes    -   (a) H, halogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   (b) —O—R^(1.3.1.1), —O—C₁₋₆-alkylene-NR^(1.3.1.2)R^(1.3.1.3),        —CO₂R^(1.3.1.1), —C(O)—NR^(1.3.1.2)R^(1.3.1.3),        —SO₂—NR^(1.3.1.2)R^(1.3.1.3), —NR^(1.3.1,2)—SO₂—R^(1.3.1.3),        —S(O)_(m)—R^(1.3.1.2), —CN, —NR^(1.3.1.2)R^(1.3.1.3),        —O—C(O)—R^(1.3.1.1) or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(1.3.2) denotes    -   (a) halogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   (b) —O—R^(1.3.2.1), —O—(CH₂)_(s)—OR^(1.3.2.1), —CO₂R^(1.3.2.1),        —S(O)_(m)—R^(1.3.2.2), —CN, —O—C(O)—R^(1.3.2.1) or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(1.3.1.1) denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, benzyl which        may be substituted by a group R^(1.3.1.1.1), or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(1.3.1.1.1) denotes halogen, HO— or C₁₋₆-alkyl-O—,-   R^(1.3.1.2) denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, or benzyl,        wherein the groups may be unsubstituted or substituted by        halogen, HO— or C₁₋₆-alkyl-O—, or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(1.3.1.3) denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, or benzyl,        wherein the groups may be unsubstituted or substituted by        halogen, HO— or C₁₋₆-alkyl-O—, or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms, or-   R^(1.3.1.2) and R^(1.3.1.3) together may also form a ring which is    selected from among azetidinyl, pyrrolidinyl, piperidinyl,    piperazinyl and morpholinyl, wherein the ring may be unsubstituted    or substituted by 1, 2 or 3 substituents R^(1.3.1.1), wherein the    substituents R^(1.3.1.1) are independent of one another,-   R^(1.3.2.1) denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, benzyl which        may be substituted by a group R^(1.3.2.1.1), or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(1.3.2.1.1) denotes halogen, HO— or C₁₋₆-alkyl-O—,-   R^(1.3.2.2) denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, or benzyl,        wherein the groups may be unsubstituted or substituted by        halogen, HO— or C₁₋₆-alkyl-O—, or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(1.3.2.3) denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, or benzyl,        wherein the groups may be unsubstituted or substituted by        halogen, HO— or C₁₋₆-alkyl-O—, or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms, or-   R^(1.3.2.2) and R^(1.3.2.3) together may also form a ring which is    selected from among azetidinyl, pyrrolidinyl, piperidinyl,    piperazinyl and morpholinyl, wherein the ring may be unsubstituted    or substituted by 1, 2 or 3 substituents R^(1.3.2.1), wherein the    substituents R^(1.3.2.1) are independent of one another,-   m denotes one of the numbers 0, 1 or 2 and-   s denotes one of the numbers 1, 2 or 3,    the tautomers, the diastereomers, the enantiomers, the hydrates, the    mixtures thereof and the salts thereof as well as the hydrates of    the salts, particularly the physiologically acceptable salts thereof    with inorganic or organic acids or bases.

A fifth embodiment of the present invention comprises the compounds ofthe above general formulae Ia and Ib, wherein R², R³, R⁴ and R⁵ aredefined as hereinbefore in the first embodiment and

-   R¹ denotes a group of general formula

wherein

-   R^(1.1) denotes    -   (a) H,    -   (b) C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl,    -   (c) a C₁₋₃-alkyl- or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(1.3) independently of one another denote    -   (a) H, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   (b) a phenyl group optionally substituted by 1, 2 or 3        substituents R^(1.3.2), wherein the substituents R^(1.3.2) may        be identical or different,    -   (c) a heteroaryl group optionally substituted by 1, 2 or 3        substituents R^(1.3.2) which is selected from among        benzimidazole, benzothiophene, furan, imidazole, indole,        isoxazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine,        pyrimidine, pyrrole, thiazole, thiophene and triazole, wherein        the substituents R^(1.3.2) may be identical or different,    -   (d) a heterocyclic group optionally substituted by 1, 2 or 3        substituents R^(1.3.2), wherein the substituents R^(1.3.2) may        be identical or different,-   R^(1.3.1) denotes    -   (a) H, halogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   (b) —O—R^(1.3.1.1), —O—C₁₋₆-alkylene-NR^(1.3.1.2)R^(1.3.1.3),        —CO₂R^(1.3.1.1), —C(O)—NR^(1.3.1.2)R^(1.3.1.3),        —SO₂—NR^(1.3.1.2)R^(1.3.1.3), —NR^(1.3.1,2)—SO₂—R^(1.3.1.3),        —S(O)_(m)—R^(1.3.1.2), —CN, —NR^(1.3.1.2)R^(1.3.1.3),        —O—C(O)—R^(1.3.1.1) or    -   (c) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(1.3.2) denotes    -   (a) halogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl,    -   (b) —O—R^(1.3.2.1), —O—(CH₂)_(s)—O—R^(1.3.2.1), —CO₂R^(1.3.2.1),        —S(O)_(m)—R^(1.3.2.2), —CN, —O—C(O)—R^(1.3.2.1) or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(1.3.1.1) denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, benzyl which        may be substituted by a group R^(1.3.1.1.1), or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(1.3.1.1.1) denotes HO— or C₁₋₆-alkyl-O—,-   R^(1.3.1.2) denotes    -   (a) H,    -   (b) C₁₋₃-alkyl, phenyl or benzyl, wherein the groups may be        unsubstituted or substituted by halogen, HO— or H₃C—O—,-   R^(1.3.1.3) denotes    -   (a) H,    -   (b) C₁₋₃-alkyl, phenyl or benzyl, wherein the groups may be        unsubstituted or substituted by halogen, HO— or H₃C—O—, or-   R^(1.3.1.2) and R^(1.3.1.3) together may also form a ring which is    selected from among azetidinyl, pyrrolidinyl, piperidinyl,    piperazinyl and morpholinyl, wherein the ring may be unsubstituted    or substituted by a substituent R^(1.3.1.1),-   R^(1.3.2.1) denotes    -   (a) H,    -   (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, benzyl which        may be substituted by a group R^(1.3.2.1.1), or    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(1.3.2.1.1) denotes HO— or C₁₋₆-alkyl-O—,-   R^(1.3.2.2) denotes    -   (a) H,    -   (b) C₁₋₃-alkyl, phenyl or benzyl, wherein the groups may be        unsubstituted or substituted by halogen, HO— or H₃C—O—,-   R^(1.3.23) denotes    -   (a) H,    -   (b) C₁₋₃-alkyl, phenyl or benzyl, wherein the groups may be        unsubstituted or substituted by halogen, HO— or H₃C—O—, or-   R^(1.3.2.2) and R^(1.3.2.3) together may also form a ring which is    selected from among azetidinyl, pyrrolidinyl, piperidinyl,    piperazinyl and morpholinyl, wherein the ring may be unsubstituted    or substituted by a substituent R^(1.3.2.1),-   m denotes one of the numbers 0, 1 or 2, and-   s denotes one of the numbers 1, 2 or 3,    the tautomers, the diastereomers, the enantiomers, the hydrates, the    mixtures thereof and the salts thereof as well as the hydrates of    the salts, particularly the physiologically acceptable salts thereof    with inorganic or organic acids or bases.

A sixth embodiment of the present invention comprises the compounds ofthe above general formulae Ia and Ib, wherein R², R³, R⁴ and R⁵ aredefined as hereinbefore in the first embodiment and

-   R¹ denotes a group selected from

the tautomers, the diastereomers, the enantiomers, the hydrates, themixtures thereof and the salts thereof as well as the hydrates of thesalts, particularly the physiologically acceptable salts thereof withinorganic or organic acids or bases.

A seventh embodiment of the present invention comprises the compounds ofthe above general formulae Ia and Ib, wherein R¹, R³, R⁴ and R⁵ aredefined as hereinbefore in the first, second, third, fourth, fifth,sixth or seventh embodiment and R² denotes a hydrogen atom,

the tautomers, the diastereomers, the enantiomers, the hydrates, themixtures thereof and the salts thereof as well as the hydrates of thesalts, particularly the physiologically acceptable salts thereof withinorganic or organic acids or bases.

An eighth embodiment of the present invention comprises the compounds ofthe above general formulae Ia and Ib, wherein R¹, R² and R⁵ are definedas hereinbefore in the first, second, third, fourth, fifth, sixth,seventh or eighth embodiment and

-   R³ denotes    -   (a) H,    -   (b) C₁₋₆-alkyl,    -   (c) a C₃₋₆-cycloalkyl group substituted by one or two groups        R^(3.2),    -   (d) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(3.2) independently of one another denote    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl,    -   (c) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R⁴ denotes    -   (a) H,    -   (b) C₁₋₆-alkylene-R^(4.1),    -   (c) a C₃₋₆-cycloalkyl group substituted by one or two groups        R^(4.2),    -   (d) a C₅₋₇-cycloalkenyl group substituted by one or two groups        R^(4.2),    -   (e) an aryl group substituted by one or two groups R^(4.2),    -   (f) a C₅₋₇-cycloalkyl group which may be fused to an aryl- or        heteroaryl group, while the resultant bicyclic group is        additionally substituted by one or two groups R^(4.2), or    -   (g) a heteroaryl group substituted by one or two groups R^(4.2),-   R^(4.1) denotes    -   (a) H,    -   (b) a phenyl group substituted by the groups R^(4.1.1) and        R^(4.1.2),    -   (c) a heteroaryl group substituted by the groups R^(4.1.1) and        R^(4.1.2),-   R^(4.1.1) denotes    -   (a) H,    -   (c) halogen, C₁₋₃-alkyl, —OH, —CN, —O—C₁₋₃-alkyl,        —NR^(4.1.1.1)R^(4.1.1.2), —S—C₁₋₃-alkyl,        —NR^(4.1.1.1)—C(O)—C₁₋₃-alkyl, —C(O)—NR^(4.1.1.1)R^(4.1.1.2),        C(O)—O—R^(4.1.1.3),    -   (d) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(4.1.1.1) denotes H, C₁₋₃-alkyl,-   R^(4.1.1.2) denotes H, C₁₋₃-alkyl, or-   R^(4.1.1.1) and R^(4.1.1.2) together with the nitrogen atom to which    they are bound also denote a group selected from morpholinyl,    thiomorpholinyl, piperidinyl, piperazinyl, pyrrolidinyl and    azetidinyl,-   R^(4.1.1.3) denotes H, C₁₋₃-alkyl,-   R^(4.1.2) denotes    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl,    -   (c) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms, or-   R^(4.2) independently of one another denote    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —CN, —O—C₁₋₃-alkyl,        —NR^(4.2.1)R^(4.2.2), —S—C₁₋₆-alkyl,        —NR^(4.2.1)—C(O)—C₁₋₃-alkyl, —C(O)—NR^(4.2.1)R^(4.2.2),        —C(O)—O—R^(4.2.3),    -   (c) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(4.2.1) denotes H, C₁₋₃-alkyl and-   R^(4.2.2) denotes H, C₁₋₃-alkyl, or-   R^(4.2.1) and R^(4.2.2) together with the nitrogen atom to which    they are bound also denote a group which is selected from among    morpholinyl, thiomorpholinyl, piperidinyl, piperidonyl, piperazinyl,    pyrrolidinyl and azetidinyl, and which may additionally be    substituted by one or two groups selected from F, —OH,    —O—C₁₋₃-alkyl, —OCF₃, C₁₋₃-alkyl and CF₃,-   R^(4.2.3) denotes H, C₁₋₃-alkyl,-   R³ and R⁴ together with the nitrogen atom to which they are bound    denote:    -   (a) a saturated 5-, 6- or 7-membered heterocyclic group which is        substituted at a carbon atom by a group R^(4.3) or by two groups        R^(4.3) and R^(4.4),    -   (b) a saturated 5-, 6- or 7-membered heterocyclic group which is        substituted at two adjacent carbon atoms by in each case a group        R^(4.3) and R^(4.4),    -   (c) a saturated 5-, 6- or 7-membered heterocyclic group which is        substituted at a carbon atom by a group R^(4.3) or by two groups        R^(4.3) and R^(4.4) and is additionally fused to a 5-, 6- or        7-membered cycloalkyl or heterocyclyl group, while the fused-on        cycloalkyl or heterocyclyl group is substituted by 1, 2 or 3        groups R^(4.5),    -   (d) a monounsaturated 5-, 6- or 7-membered heterocyclic group        which is substituted at a carbon atom by a group R^(4.3) or by        two groups R^(4.3) and R^(4.4) and is additionally fused to a        phenyl group, while the fused-on phenyl group is substituted by        1, 2 or 3 groups R^(4.5),    -   (e) a monounsaturated 5-, 6- or 7-membered heterocyclic group        which is substituted at a carbon atom by a group R^(4.3) or by        two groups R^(4.3) and R^(4.4) and is additionally fused to a 5-        or 6-membered heteroaryl group, while the fused-on heteroaryl        group is substituted by 1, 2 or 3 groups R^(4.5), or    -   (f) a heteroaryl group which is substituted at 1, 2 or 3 carbon        atoms by a group R^(4.5),-   R^(4.3) denotes H, C₁₋₃-alkyl, phenyl, —C₁₋₃-alkylene-R^(4.3.1),    C₁₋₃-alkyl-O—C(O)—, HO—C(O)—, F, —O—C₁₋₃-alkyl, —OH, —CN-   R^(4.3.1) denotes H, C₁₋₃-alkyl-O—C(O)—, —NH₂, (C₁₋₄-alkyl)-NH—,    (C₁₋₄-alkyl)₂N—, heterocyclyl,-   R^(4.4) denotes    -   (a) H, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl or    -   (b) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(4.3) and R^(4.4) together with the carbon atoms to which they are    bound also denote a C₃₋₆-cycloalkyl, C₅₋₆-cycloalkenyl or    heterocyclyl group,-   R^(4.5) independently of one another denote    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, —NH₂, —CN,        —C(O)—O—R^(4.5.1), —C(O)—NR^(4.5.2)R^(4.5.3),    -   (c) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,    -   (d) phenyl,-   R^(4.5.1) denotes H, C₁₋₃-alkyl,-   R^(4.5.2) denotes H, C₁₋₃-alkyl and-   R^(4.5.3) denotes H, C₁₋₃-alkyl,    the tautomers, the diastereomers, the enantiomers, the hydrates, the    mixtures thereof and the salts thereof as well as the hydrates of    the salts, particularly the physiologically acceptable salts thereof    with inorganic or organic acids or bases.

A ninth embodiment of the present invention comprises the compounds ofthe above general formulae Ia and Ib, wherein R¹, R² and R⁵ are definedas hereinbefore in the first, second, third, fourth, fifth, sixth,seventh or eighth embodiment and

-   R³ denotes    -   (a) H,    -   (b) C₁₋₆-alkyl,    -   (c) a C₃₋₆-cycloalkyl substituted by one or two groups R^(3.2),        or    -   (d) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(3.2) independently of one another denote    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl,    -   (c) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R⁴ denotes    -   (a) H,    -   (b) C₁₋₆-alkylene-R^(4.1),    -   (c) a C₃₋₆-cycloalkyl group substituted by one or two groups        R^(4.2),    -   (d) a C₅₋₇-cycloalkenyl group substituted by one or two groups        R^(4.2),    -   (e) an aryl group substituted by one or two groups R^(4.2),    -   (f) a C₅₋₆-cycloalkyl group which may be fused to a phenyl,        thiazole or thienyl group, while the resultant bicyclic group is        additionally substituted by one or two groups R^(4.2),-   R^(4.1) denotes    -   (a) H,    -   (b) a phenyl group substituted by the groups R^(4.1.1) and        R^(4.1.2),-   R^(4.1.1) denotes    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, —CN,        —C(O)—O—R^(4.1.1.3),    -   (c) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(4.1.1.3) denotes H, C₁₋₃-alkyl,-   R^(4.1.2) denotes    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl,    -   (c) a C₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms, or-   R^(4.2) independently of one another denote    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, —CN, —NH₂,        —O—C(O)—C₁₋₃-alkyl,    -   (c) a C₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R³ and R⁴ together with the nitrogen atom to which they are bound    denote:    -   (a) a saturated 5- or 6-membered heterocyclic group which is        substituted at a carbon atom by a group R^(4.3) or by two groups        R^(4.3) and R^(4.4),    -   (b) a saturated 5- or 6-membered heterocyclic group which is        substituted at two adjacent carbon atoms by in each case a group        R^(4.3) and R^(4.4),    -   (c) a saturated 5-, 6- or 7-membered heterocyclic group which is        substituted at a carbon atom by a group R^(4.3) or by two groups        R^(4.3) and R^(4.4) and is additionally fused to a 5-, 6- or        7-membered cycloalkyl or heterocyclyl group, while the fused-on        cycloalkyl or heterocyclyl group is substituted by 1, 2 or 3        groups R^(4.5),    -   (d) a monounsaturated 5-, 6- or 7-membered heterocyclic group        which is substituted at a carbon atom by a group R^(4.3) or by        two groups R^(4.3) and R^(4.4) and is additionally fused to a        phenyl group, while the fused-on phenyl group is substituted by        1, 2 or 3 groups R^(4.5),    -   (e) a monounsaturated 5-, 6- or 7-membered heterocyclic group        which is substituted at a carbon atom by a group R^(4.3) or by        two groups R^(4.3) and R^(4.4) and is additionally fused to a 5-        or 6-membered heteroaryl group, while the fused-on heteroaryl        group is substituted by 1, 2 or 3 groups R^(4.5) and is selected        from among

-   -   (f) a heteroaryl group which is substituted at 1, 2 or 3 carbon        atoms by in each case a group R^(4.5),

-   R^(4.3) denotes H, C₁₋₃-alkyl, phenyl, —C₁₋₃-alkylene-R^(4.3.1),    C₁₋₃-alkyl-O—C(O)—, HO—C(O)—, F, —O—C₁₋₃-alkyl, —OH, —CN

-   R^(4.3.1) denotes H, C₁₋₃-alkyl-O—C(O)—, —NH₂, (C₁₋₄-alkyl)-NH—,    (C₁₋₄-alkyl)₂N—, morpholinyl, thiomorpholinyl, piperidinyl,    pyrrolidinyl, azetidinyl,

-   R^(4.4) denotes    -   (a) H, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl or    -   (b) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,

-   R^(4.3) and R^(4.4) together with the carbon atoms to which they are    bound also denote a C₃₋₆-cycloalkyl or heterocyclyl group, and

-   R^(4.5) independently of one another denote    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, —NH₂, —CN,    -   (c) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms, or    -   (d) phenyl,        the tautomers, the diastereomers, the enantiomers, the hydrates,        the mixtures thereof and the salts thereof as well as the        hydrates of the salts, particularly the physiologically        acceptable salts thereof with inorganic or organic acids or        bases.

A tenth embodiment of the present invention comprises the compounds ofthe above general formulae Ia and Ib, wherein R¹, R² and R⁵ are definedas hereinbefore in the first, second, third, fourth, fifth, sixth,seventh or eighth embodiment and

-   R³ denotes    -   (a) H,    -   (b) C₁₋₆-alkyl,    -   (c) a C₃₋₆-cycloalkyl group substituted by one or two groups        R^(3.2), or    -   (d) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms,-   R^(3.2) independently of one another denote    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl,    -   (c) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R⁴ denotes    -   (a) H,    -   (b) C₁₋₆-alkylene-R^(4.1),    -   (c) a C₃₋₆-cycloalkyl group substituted by one or two groups        R^(4.2),    -   (d) a C₅₋₇-cycloalkenyl group substituted by one or two groups        R^(4.2),    -   (e) a phenyl group substituted by one or two groups R^(4.2),    -   (f) a C₅₋₆-cycloalkyl group which may be fused to a phenyl,        thiazolyl or thienyl group, while the resultant bicyclic group        is additionally substituted by one or two groups R^(4.2),-   R^(4.1) denotes    -   (a) H,    -   (b) a phenyl group substituted by the groups R^(4.1.1) and        R^(4.1.2),-   R^(4.1.1) denotes    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, —CN,        —C(O)—O—R^(4.1.13),    -   (c) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,-   R^(4.1.1.3) denotes H, C₁₋₃-alkyl,-   R^(4.1.2) denotes    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl,    -   (c) a C₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms, or-   R^(4.2) denotes    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, —CN, —NH₂,    -   (c) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms, or-   R³ and R⁴ together with the nitrogen atom to which they are bound    denote:    -   (a) a saturated 5- or 6-membered heterocyclic group which is        selected from among piperidinyl, piperidinonyl, morpholinyl,        thiomorpholinyl, piperazinyl, pyrrolidinyl and pyrrolidinonyl,        and which is substituted at a carbon atom by a group R^(4.3) or        by two groups R^(4.3) and R^(4.4),    -   (b) a saturated 5- or 6-membered heterocyclic group which is        selected from among piperidinyl, piperidinonyl, morpholinyl,        thiomorpholinyl, piperazinyl, pyrrolidinyl and pyrrolidinonyl,        and which is substituted at two adjacent carbon atoms by in each        case a group R^(4.3) and R^(4.4),    -   (c) a saturated 5-, 6- or 7-membered heterocyclic group which is        selected from among piperidinyl, piperidinonyl, morpholinyl,        thiomorpholinyl, piperazinyl, pyrrolidinyl, pyrrolidinonyl,        azepanyl, diazepanyl, diazepanonyl and oxazepanyl, and which is        substituted at a carbon atom by a group R^(4.3) or by two groups        R^(4.3) and R^(4.4) and is additionally fused to a 5-, 6- or        7-membered cycloalkyl or heterocyclyl group, which is selected        from among piperidinyl, piperidinonyl, morpholinyl,        thiomorpholinyl, piperazinyl, pyrrolidinyl, pyrrolidinonyl,        azepanyl, diazepanyl, diazepanonyl and oxazepanyl, while the        fused-on cycloalkyl or heterocyclyl group is substituted by 1, 2        or 3 groups R^(4.5),    -   (d) a monounsaturated 5-, 6- or 7-membered heterocyclic group        which is selected from among

-   -   -   and which is substituted at a carbon atom by a group R^(4.3)            or by two groups R^(4.3) and R^(4.4) and is additionally            fused to a phenyl group, the fused-on phenyl group being            substituted by 1, 2 or 3 groups R^(4.5),

    -   (e) a monounsaturated 5-, 6- or 7-membered heterocyclic group        which is selected from among

-   -   -   and which is substituted at a carbon atom by a group R^(4.3)            or by two groups R^(4.3) and R^(4.4) and is additionally            fused to a 5- or 6-membered heteroaryl group, while the            fused-on heteroaryl group is substituted by 1, 2 or 3 groups            R^(4.5), and is selected from among

-   -   (f) a heteroaryl group which is selected from among indole,        isoindole, azaindole, indazole and benzimidazole, and which is        substituted at 1, 2 or 3 carbon atoms by a group R^(4.5),

-   R^(4.3) denotes H, C₁₋₃-alkyl, phenyl, —C₁₋₃-alkylene-R^(4.3.1),    C₁₋₃-alkyl-O—C(O)—, HO—C(O)—, F, —O—C₁₋₃-alkyl, —OH, —CN,

-   R^(4.3.1) denotes H, C₁₋₃-alkyl-O—C(O), —NH₂, (C₁₋₄-alkyl)-NH,    (C₁₋₄-alkyl)₂N, morpholinyl, thiomorpholinyl, piperidinyl,    pyrrolidinyl, azetidinyl,

-   R^(4.4) denotes    -   (a) H, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl or    -   (b) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms,

-   R^(4.3) and R^(4.4) together with the carbon atoms to which they are    bound also denote a C₃₋₆-cycloalkyl group or a heterocyclyl group    which is selected from among azetidinyl, pyrrolidinyl, piperidinyl    and azepanyl, and

-   R^(4.5) independently of one another denote    -   (a) H,    -   (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, —NH₂, —CN,    -   (c) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene        group is substituted by up to two fluorine atoms and each methyl        group is substituted by up to three fluorine atoms, or    -   (d) phenyl,        the tautomers, the diastereomers, the enantiomers, the hydrates,        the mixtures thereof and the salts thereof as well as the        hydrates of the salts, particularly the physiologically        acceptable salts thereof with inorganic or organic acids or        bases.

An eleventh embodiment of the present invention comprises the compoundsof the above general formulae Ia and Ib, wherein R¹, R² and R⁵ aredefined as hereinbefore in the first, second, third, fourth, fifth,sixth, seventh or eighth embodiment and

-   R³ denotes    -   (a) H,    -   (b) C₁₋₃-alkyl,    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms, and-   R⁴ denotes H or a group selected from

-   R³ and R⁴ together with the nitrogen atom to which they are bound    denote a group selected from

the tautomers, the diastereomers, the enantiomers, the hydrates, themixtures thereof and the salts thereof as well as the hydrates of thesalts, particularly the physiologically acceptable salts thereof withinorganic or organic acids or bases.

A twelfth embodiment of the present invention comprises the compounds ofthe above general formulae Ia and Ib, wherein R¹, R², R³ and R⁴ aredefined as hereinbefore in the first, second, third, fourth, fifth,sixth, seventh, eighth, ninth, tenth or eleventh embodiment and

-   R⁵ denotes H or C₁₋₃-alkyl,    the tautomers, the diastereomers, the enantiomers, the hydrates, the    mixtures thereof and the salts thereof as well as the hydrates of    the salts, particularly the physiologically acceptable salts thereof    with inorganic or organic acids or bases.

A thirteenth embodiment of the present invention comprises the compoundsof general formulae Ia and Ib wherein

-   R¹ denotes a group selected from

-   R² denotes H,-   R³ denotes    -   (a) H,    -   (b) C₁₋₃-alkyl,    -   (c) a C₁₋₃-alkyl group wherein each methylene group is        substituted by up to two fluorine atoms and each methyl group is        substituted by up to three fluorine atoms, and-   R⁴ denotes H or a group selected from

-   R³ and R⁴ together with the nitrogen atom to which they are bound    denote a group selected from

-   R⁵ denotes H or C₁₋₃-alkyl,    the tautomers, the diastereomers, the enantiomers, the hydrates, the    mixtures thereof and the salts thereof as well as the hydrates of    the salts, particularly the physiologically acceptable salts thereof    with inorganic or organic acids or bases.

The following compounds are mentioned as examples of most particularlypreferred compounds of the above general formulae Ia and Ib:

No. Structure (1)

(2)

(3)

(4)

(5)

(6)

(7)

(8)

(9)

(10)

(11)

(12)

(13)

(14)

(15)

(16)

(17)

the enantiomers, the diastereomers, the hydrates, the mixtures thereofand the salts thereof as well as the hydrates of the salts, particularlythe physiologically acceptable salts thereof with inorganic or organicacids or bases.

TERMS AND DEFINITIONS USED

The present specification of the invention is to be interpreted inaccordance with the conventions and rules of chemical bonds.

The compounds included in this invention are those that are alsochemically stable.

Unless otherwise stated, all the substituents are independent of oneanother. If for example there are a plurality of C₁₋₄-alkyl groups assubstituents in one group, in the case of three C₁₋₄-alkyl substituents,independently of one another, one may represent methyl, one ethyl andone n-propyl.

Within the scope of this application, in the definition of possiblesubstituents, these may also be represented in the form of a structuralformula. If present, an asterisk (*) in the structural formula of thesubstituent is to be understood as being the linking point to the restof the molecule. For example a phenyl group is shown as follows:

Moreover, the atom of the substituent that follows the linking point isunderstood as being the atom at position number 1.

The subject-matter of this invention also includes the compoundsaccording to the invention, including the salts thereof, wherein one ormore hydrogen atoms, for example one, two, three, four or five hydrogenatoms, are replaced by deuterium.

By the term “C₁₋₃-alkyl” (including those which are a part of othergroups) are meant branched and unbranched alkyl groups with 1 to 3carbon atoms, by the term “C₁₋₄-alkyl” are meant branched and unbranchedalkyl groups with 1 to 4 carbon atoms and by the term “C₁₋₆-alkyl” aremeant branched and unbranched alkyl groups with 1 to 6 carbon atoms.Examples include: methyl, ethyl, n-propyl, iso-propyl, n-butyl,iso-butyl, sec-butyl, tert-butyl, pentyl, neopentyl or n-hexyl. Theabbreviations may optionally also be used for the above-mentioned groupsMe, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. Unless stated otherwise, thedefinitions propyl and butyl include all the possible isomeric forms ofthe groups in question. Thus, for example, propyl includes n-propyl andiso-propyl, butyl includes iso-butyl, sec-butyl and tert-butyl etc.

By the term “C₁₋₆-alkylene” (including those which are a part of othergroups) are meant branched and unbranched alkylene groups with 1 to 6carbon atoms and by the term “C₁₋₃-alkylene” are meant branched andunbranched alkylene groups with 1 to 3 carbon atoms. Examples include:methylene, ethylene, propylene, 1-methylethylene, butylene,1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene,pentylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene,1,2-dimethylpropylene, 1,3-dimethylpropylene or hexylene. Unless statedotherwise, the definition propylene includes all the possible isomericforms of the groups in question with the same number of carbons. Thus,for example, propyl also includes 1-methylethylene and butylene includes1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene.

The definition for C_(o)-alkylene denotes a bond.

By the term “C₂₋₆-alkenyl” (including those which are a part of othergroups) are meant branched and unbranched alkenyl groups with 2 to 6carbon atoms and by the term “C₂₋₄-alkenyl” are meant branched andunbranched alkenyl groups with 2 to 4 carbon atoms, provided that theycomprise at least one double bond. Alkenyl groups with 2 to 4 carbonatoms are preferred. Examples include: ethenyl or vinyl, propenyl,butenyl, pentenyl, or hexenyl. Unless stated otherwise, the definitionspropenyl, butenyl, pentenyl and hexenyl include all the possibleisomeric forms of the groups in question. Thus, for example, propenylincludes 1-propenyl and 2-propenyl, butenyl includes 1-, 2- and3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl etc.

By the term “C₂₋₆-alkynyl” (including those which are a part of othergroups) are meant branched and unbranched alkynyl groups with 2 to 6carbon atoms and by the term “C₂₋₄-alkynyl” are meant branched andunbranched alkynyl groups with 2 to 4 carbon atoms, provided that theycomprise at least one triple bond. Examples include: ethynyl, propynyl,butynyl, pentynyl, or hexynyl. Unless stated otherwise, the definitionspropynyl, butynyl, pentynyl and hexynyl include all the possibleisomeric forms of the groups in question. Thus, for example propynylincludes 1-propynyl and 2-propynyl, butynyl includes 1-, 2- and3-butynyl, 1-methyl-1-propynyl, 1-methyl-2-propynyl etc.

By the term “C₃₋₆-cycloalkyl” (including those which are a part of othergroups) are meant cyclic alkyl groups with 3 to 6 carbon atoms and bythe term “C₅₋₆-cycloalkyl” are meant cyclic alkyl groups with 5 to 6carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl. Unless otherwise stated, the cyclic alkyl groups may besubstituted by one or more groups selected from among methyl, ethyl,iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.

By the term “C₅₋₆-cycloalkenyl” (including those which are a part ofother groups) are meant cyclic alkenyl groups with 5 or 6 carbon atoms,which contain an unsaturated bond. Examples include: cyclopentenyl orcyclohexenyl. Unless otherwise stated, the cyclic alkenyl groups may besubstituted by one or more groups selected from among methyl, ethyl,iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.

By the term “heterocyclyl” or “heterocyclic group” are meant, unlessotherwise described in the definitions, stable 5-, 6- or 7-memberedmonocyclic or 8-, 9-, 10- or 11-membered bicyclic heterocyclic ringsystems, which do not form an aromatic ring system in at least one ringand in addition to carbon atoms may carry one to four heteroatomsselected from among nitrogen, oxygen and sulphur. The two nitrogen atomsand also sulphur atoms may optionally be oxidised and nitrogen atoms maybe quaternised. The heterocyclic ring may contain one or two carbonyl,thiocarbonyl or cyanoimino groups adjacent to a nitrogen atom. Theheterocycles mentioned previously may be linked to the rest of themolecule via a carbon atom or a nitrogen atom.

Unless otherwise stated, the heterocycles may be substituted by one ormore groups selected from among:

-   -   (a) OH, NO₂, CN, OCF₃, OCHF₂, OCH₂F, NH₂,    -   (b) halogen, preferably fluorine or chlorine,    -   (c) C₁₋₆-alkyl, preferably C₁₋₃-alkyl, particularly preferably        ethyl, methyl, iso-propyl or tert-butyl,    -   (d) —SO₂—O—C₁₋₃-alkyl, preferably —O-methyl,    -   (e) —O—C₁₋₃-alkyl, preferably —O-methyl or —O-ethyl,    -   (f) COOH, COO—C₁₋₃-alkyl, preferably CO—O-methyl or CO—O-ethyl,        while the groups may be identical or different.

The following compounds are mentioned by way of example, but theinvention is not restricted to them: azetidine, oxetane, thietane,thietane dioxide, tetrahydrofuran, dihydrofuran, dioxolane,imidazolidine, imidazoline, imidazolidinone, dihydroimidazolone,oxazoline, oxazolidine, oxazolidinone, pyrrolidinone, dihydropyrazole,pyrrolidine, pyrroline, morpholine, tetrahydropyridine, dihydropyran,tetrahydropyran, dioxane, piperazine, piperidine, piperazinone,piperidinone, pyran, thiomorpholine-S-oxide, thiomorpholine-S-dioxide,thiomorpholine, dihydroxazine, morpholinedione, morpholinethione,perhydrothiazinedioxide, {acute over (ε)}-caprolactam, oxazepanone,diazepanone, thiazepanone, perhydroazepine, dihydroquinazolinone,dihydroindole, dihydroisoindole, benzoxazolone, benzimidazolone,chromanone, tetrahydroquinoline, tetrahydrobenzoxazole,tetrahydrobenzisoxazole, tetrahydrobenzothiophene,tetrahydrothieno-pyridine, tetrahydrobenzofuran,tetrahydro-oxazolopyridine, tetrahydro-isoxazolopyridine.

The following heterocycles are preferred according to the invention:

By the term “aryl” (including those which are a part of other groups)are meant monocyclic aromatic ring systems with 6 carbon atoms orbicyclic aromatic ring systems with 10 carbon atoms. Examples includephenyl, 1-naphthyl or 2-naphthyl; the preferred aryl group is phenyl.

Unless otherwise stated, the aromatic groups may be substituted by oneor more groups selected from among:

-   -   (a) OH, NO₂, CN, OCF₃, OCHF₂, OCH₂F, NH₂,    -   (b) halogen, preferably fluorine or chlorine,    -   (c) C₁₋₆-alkyl, preferably C₁₋₃-alkyl, particularly preferably        ethyl, methyl, iso-propyl or tert-butyl,    -   (d) —SO₂—O—C₁₋₃-alkyl, preferably —O-methyl,    -   (e) —O—C₁₋₃-alkyl, preferably —O-methyl or —O-ethyl,    -   (f) COOH, CO—O—C₁₋₃-alkyl, preferably CO—O-methyl or CO—O-ethyl,        while the groups may be identical or different.

By the term “heteroaryl” are meant stable five- or six-memberedheterocyclic aromatic groups or 8- to 10-membered bicyclic heteroarylrings that may contain in each ring one, two or three heteroatoms,selected from among oxygen, sulphur and nitrogen, and additionallysufficient conjugated double bonds to form an aromatic system. Examplesof five- or six-membered heterocyclic aromatic groups are as follows,but the invention is not restricted to these:

furan, pyrrole, thiophene, pyrazole, imidazole, oxazole, thiazole,isothiazole, isoxazole, oxadiazole, triazole, tetrazole, furazan,thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, triazine.

The following five-membered heterocyclic aromatic groups are preferredaccording to the invention:

The following six-membered heterocyclic aromatic groups are preferredaccording to the invention:

Examples of 9- or 10-membered bicyclic heteroaryl rings are as follows,but the invention is not restricted to these:

indole, isoindole, indazole, indolizine, benzofuran, benzthiophene,benzimidazole, benzoxazole, benzothiazole, benzotriazole, benzisoxazole,benzisothiazole, quinoline, isoquinoline, cinnoline, phthalazine,quinoxaline, quinazoline, pyridopyrimidine, pyridopyrazine,pyridopyridazine, pyrimidopyrimidine, pteridine, purine, quinolizine,benzoxazolecarbonitrile, quinoline, isoquinoline, quinolizine,pteridine, purine, quinolizine, benzoxazole-carbonitrile.

The following bicyclic heteroaryl rings are preferred according to thisinvention:

Unless otherwise stated, the heteroaryls previously mentioned may besubstituted by one or more groups selected from among:

-   -   (a) OH, NO₂, CN, OCF₃, OCHF₂, OCH₂F, NH₂,    -   (b) halogen, preferably fluorine or chlorine,    -   (c) C₁₋₆-alkyl, preferably C₁₋₃-alkyl, particularly preferably        ethyl, methyl, iso-propyl or tert-butyl,    -   (d) —SO₂—O—C₁₋₃-alkyl, preferably —O-methyl,    -   (e) —O—C₁₋₃-alkyl, preferably —O-methyl or —O-ethyl,    -   (f) COOH, CO—O—C₁₋₃-alkyl, preferably CO—O-methyl or CO—O-ethyl,        while the groups may be identical or different.

Bicyclic heteroaryl rings may preferably be substituted in the phenylgroup.

By the term “halogen” are meant fluorine, chlorine, bromine or iodineatoms.

Compounds of general formulae Ia and Ib may have acid groups, mainlycarboxyl groups, and/or basic groups such as e.g. amino functions.Compounds of general formulae Ia and Ib may therefore be present asinternal salts, as salts with pharmaceutically useable inorganic acidssuch as for example hydrobromic acid, phosphoric acid, nitric acid,hydrochloric acid, sulphuric acid, methanesulphonic acid,ethanesulphonic acid, benzenesulphonic acid, p-toluenesulphonic acid ororganic acids such as for example malic acid, succinic acid, aceticacid, fumaric acid, maleic acid, mandelic acid, lactic acid, tartaricacid, citric acid or as salts with pharmaceutically useable bases suchas alkali or alkaline earth metal hydroxides, e.g. sodium hydroxide orpotassium hydroxide, or carbonates, ammonia, zinc or ammonium hydroxidesor organic amines such as e.g. diethylamine, triethylamine,ethanolamine, diethanolamine, triethanolamine, cyclohexylamine,dicyclohexylamine, inter alia.

The compounds according to the invention may be present as racemates,provided that they have only one chiral element, but may also beobtained as pure enantiomers, i.e. in the (R) or (S) form.

However, the application also includes the individual diastereomericpairs of antipodes or mixtures thereof, which are obtained if there ismore than one chiral element in the compounds of general formulae Ia andIb, as well as the individual optically active enantiomers of which theabove-mentioned racemates are made up.

The invention relates to the compounds in question, optionally in theform of the individual optical isomers, mixtures of the individualenantiomers or racemates, in the form of the tautomers as well as in theform of the free bases or the corresponding acid addition salts withpharmacologically acceptable acids.

So-called prodrugs of compounds of general formulae Ia and Ib are alsoencompassed by this invention. The term prodrug is used to denote anymolecule that releases the active principle of general formulae Ia andIb in-vivo after administration to mammals. The prodrug may have littleor no pharmacological activity per se, but releases the active principleof general formulae Ia and Ib in-vivo after administration and this hasthe activity described. Prodrugs for compounds of general formulae Iaand Ib may be prepared by modifying suitable functional groups in thecompound of general formulae Ia and Ib, as known to the skilled man inthis field. (H. Bundgaard (Editor), Design of Prodrugs. (1986),Elsevier)

This invention also includes those metabolites that are derived from thecompounds of general formulae Ia and Ib. By metabolites are meant, inthis context, compounds that are formed in-vivo from the compound ofgeneral formulae Ia and Ib after administration. Examples of metabolitesinclude:

-   -   methyl groups of the compound of general formulae Ia and Ib may        be converted into the corresponding hydroxymethyl groups.        (—CH₃->—CH₂OH)    -   alkoxy groups of the compound of general formulae Ia and Ib may        be converted into the corresponding hydroxyl groups. (—OR->—OH)    -   secondary amines of the compound of general formulae Ia and Ib        may be converted into the corresponding primary amines.        (—NR₁R₂->—NHR₁ or —NHR₂)    -   nitrogen atoms of the compound of general formulae Ia and Ib may        be converted into the corresponding nitrogen oxides.        (═N—->═N⁺—(O⁻)—)

Methods Of Preparation

The invention also relates to a process for preparing the compounds ofgeneral formulae Ia and Ib

wherein R¹, R², R³, R⁴ and R⁵ are as hereinbefore defined.

Some methods of preparing the compounds of general formula Ia accordingto the invention are illustrated in the following synthesis schemes andExamples.

The regioisomeric compounds of general formula Ib, wherein R¹, R², R³,R⁴ and R⁵ are as hereinbefore defined may be prepared analogously to themethods described hereinafter. In some cases the order of carrying outthe reaction schemes may be varied in order to simplify the reactions orprevent unwanted by-products. The Examples that follow are provided tomake the invention fully comprehensible. The Examples are intended toillustrate the invention and should in no way restrict it.

The compounds according to the invention may be prepared according tothe schemes and specific examples provided or correspondingmodifications thereof. Modifications to these reactions which are knownto the skilled man but not described in detail here may also beimplemented. The general methods of preparing the compounds according tothe invention will become apparent to the skilled man from a study ofthe following schemes.

Starting compounds are commercially available or are prepared byprocesses which are described in the literature, known in the art or asdescribed herein. Before the reaction is carried out correspondingfunctional groups in the compounds may be protected by conventionalprotective groups. These protective groups may be cleaved again at asuitable stage within the reaction sequence using methods familiar tothe skilled man.

In the reactions described below, any reactive groups present such ashydroxy, carboxy, amino, alkylamino, amide or imino groups may beprotected during the reaction by conventional protective groups that arecleaved again after the reaction.

For example

-   -   a suitable protective group for a hydroxy group may be the        methoxy, benzyloxy, trimethylsilyl, acetyl, benzoyl,        tert.-butyl, trityl, benzyl or tetrahydropyranyl group,    -   suitable protective groups for a carboxyl group may be the        trimethylsilyl, methyl, ethyl, tert.-butyl, benzyl or        tetrahydropyranyl group, and    -   suitable protective groups for an amide group may be the        N-methoxymethyl-(MOM), N-benzyloxymethyl (BOM),        N-(trimethylsilyl)ethoxymethyl (SEM),        N-tert-butyldimethylsiloxymethyl, N-tert-butyldimethylsilyl        (TBDMS), N-triisopropylsilyl-(TIPS), N-benzyl, N-4-methoxybenzyl        (PMB), N-triphenylmethyl (Trt), N-tert-butoxycarbonyl (BOC),        N-benzyloxycarbonyl (Cbz) or N-trimethylsilylethylsulphonyl        (SES)    -   a suitable protective group for an amino, alkylamino or imino        group may be the acetyl, trifluoroacetyl, benzoyl,        ethoxycarbonyl, tert.-butoxycarbonyl, benzyloxycarbonyl, benzyl,        methoxybenzyl or 2,4-dim ethoxybenzyl group and additionally,        for the amino group, the phthalyl group.

Other protective groups and their cleavage are described in T. W.Greene, P. G. M. Wuts, “Protective Groups in Organic Synthesis”, Wiley,1991 and 1999.

Any protecting group used is optionally subsequently cleaved for exampleby hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water,tetrahydrofuran/water or dioxane/water, in the presence of an acid suchas trifluoroacetic acid, hydrochloric acid or sulphuric acid or in thepresence of an alkali metal base such as lithium hydroxide, sodiumhydroxide or potassium hydroxide, or by ether splitting, e.g. in thepresence of iodotrimethylsilane, at temperatures between 0 and 100° C.,preferably at temperatures between 10 and 50° C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved,for example, hydrogenolytically, e.g. with hydrogen in the presence of acatalyst such as palladium/charcoal in a solvent such as methanol,ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone orglacial acetic acid, optionally with the addition of an acid such ashydrochloric acid at temperatures between 0 and 50° C., but preferablyat ambient temperature, and at a hydrogen pressure of 1 to 7 bar, butpreferably 1 to 5 bar.

A methoxybenzyl group may also be cleaved in the presence of anoxidising agent such as cerium(IV)ammonium nitrate in a solvent such asmethylene chloride, acetonitrile or acetonitrile/water at temperaturesof between 0 and 50° C., but preferably at ambient temperature.

A methoxy group is conveniently cleaved in the presence of borontribromide in a solvent such as methylene chloride at temperaturesbetween −35 and −25° C. Alternatively a methoxy group may also becleaved using Brønsted acids with or without a solvent. Preferablypyridine hydrochloride is used at elevated temperatures without asolvent.

A 2,4-dimethoxybenzyl group is preferably cleaved in trifluoroaceticacid in the presence of anisole.

A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved bytreating with an acid such as trifluoroacetic acid or hydrochloric acid,optionally using a solvent such as methylene chloride, dioxan or ether.

A phthalyl group is preferably cleaved in the presence of hydrazine or aprimary amine such as methylamine, ethylamine or n-butylamine in asolvent such as methanol, ethanol, isopropanol, toluene/water or dioxanat temperatures between 20 and 50° C.

A methoxymethyl group may be cleaved in the presence of an acid such asconcentrated hydrochloric acid in a solvent such as dimethoxyethane.Alternatively an acid such as trifluoroacetic acid may also be usedwithout a solvent.

An N-(trimethylsilyl)ethoxymethyl group may be cleaved in the presenceof TBAF and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone.Alternatively the SEM protective group may also be cleaved with an acidsuch as hydrogen chloride in an organic solvent such as dioxane orethanol.

An allyloxycarbonyl group is cleaved by treating with a catalytic amountof tetrakis-(triphenylphosphine)-palladium(0), preferably in a solventsuch as tetrahydrofuran and preferably in the presence of an excess of abase such as morpholine at temperatures between 0 and 100° C.,preferably at ambient temperature and under an inert gas, or by treatingwith a catalytic amount of tris-(triphenylphosphine)-rhodium(I)chloridein a solvent such as aqueous ethanol and optionally in the presence of abase such as 1,4-diazabicyclo[2,2,2]octane at temperatures between 20and 70° C.

The following methods of preparing the compounds of general formula Iaaccording to the invention wherein R¹, R², R³, R⁴ and R⁵ are ashereinbefore defined and their precursors have proved particularlysuitable:

The preparation of a compound of general formula (I-4), wherein R¹, R²,R³ and R⁴ are as hereinbefore defined and R⁵ denotes a hydrogen atom, isshown in Scheme 1. A compound of general formula (1-1), wherein R¹ andR² are as hereinbefore defined, may be reacted with a compound ofgeneral formula (1-2), wherein R³ and R⁴ are as hereinbefore defined, LGdenotes a leaving group and PG denotes a protective group. The leavinggroup LG may be halides, preferably chlorides and bromides, —SO₂CH₃,—OSO₂CH₃, —OSO₂C₆H₄—CH₃ or —S—CH₃ (—S—CH₃ requires further reaction withan organic peroxide in order to be able to be converted into the actualleaving group) etc., but the list is not restrictive. It is mostparticularly preferable to use chlorides. Protective groups PG for thehydroxy functionality are known to the skilled man or are described inthe literature (T. W. Greene, P. G. M. Wuts, “Protective Groups inOrganic Synthesis”, Wiley, 1999). The methoxy protecting group is mostparticularly preferred.

The reaction may be carried out in an inert solvent using an auxiliarybase in a temperature range from 0° C. to the reflux temperature of thesolvent. The reaction is carried out in a suitable inert solvent, suchas tetrahydrofuran, toluene, xylene, dialkylformamide (particularlypreferably dimethylformamide), cyclic amides (particularly preferablyN-methylpyrrolidone), 1,4-dioxane, acetonitrile or in mixtures ofsolvents. Examples of suitable auxiliary bases are tertiary amines suchas triethylamine or ethyldiisopropylamine, alkali metal carbonates suchas potassium carbonate or sodium carbonate, sodium hydride (NaH) orlithium diisopropylamide (LDA). The inert solvent used must becompatible with the base used. Preferably the reaction is carried out inN-methylpyrrolidone, at temperatures between ambient temperature and thereflux temperature of the solvent in the presence of potassium carbonateas auxiliary base. Starting from a compound of general formula (I-3),wherein R¹, R², R³ and R⁴ are as hereinbefore defined and PG denotes aprotective group, a compound of general formula (1-4), wherein R¹, R²,R³ and R⁴ are as hereinbefore defined and R⁵ denotes a hydrogen atom,may be obtained by ether cleavage as shown in Scheme 1. Ethers can becleaved with Brønsted acids or Lewis acids. It is most preferable toreact compounds of general formula (I-3) with pyridine hydrochloridewithout a solvent at elevated temperatures. Protective groups PG for thehydroxy functionality are known to the skilled man or are described inthe literature (T. W. Greene, P. G. M. Wuts, “Protective Groups inOrganic Synthesis”, Wiley, 1999). The methoxy protecting group is mostparticularly preferred.

Compounds of general formula (2-3), wherein R³ and R⁴ are ashereinbefore defined, LG represents a leaving group and PG represents aprotective group, may be synthesised analogously to Scheme 2. Theleaving group LG may be halides, preferably chlorides and bromides,—SO₂CH₃, —OSO₂CH₃, —OSO₂C₆H₄—CH₃ or —S—CH₃ (—S—CH₃ requires furtherreaction with an organic peroxide in order to be able to be convertedinto the actual leaving group) etc., but the list is not restrictive. Itis most particularly preferable to use chlorides. Protective groups PGfor the hydroxy functionality are known to the skilled man or aredescribed in the literature (T. W. Greene, P. G. M. Wuts, “ProtectiveGroups in Organic Synthesis”, Wiley, 1999). It is most preferable toprotect the hydroxy functionality with a methoxy protecting group.

Carboxylic acids of general formula (2-1) wherein PG represents aprotective group and LG denotes a leaving group, may be reacted withcompounds of general formula (2-2), wherein R³ and R⁴ are ashereinbefore defined, using standard peptide coupling reagents and abase in an inert solvent to obtain amides of general formula (2-3) (cfe.g. Houben-Weyl, Methoden der Organischen Chemie, vol. 15/2). Inertsolvents that may be used are dimethylformamide, N-methylpyrrolidone,dim ethoxyethane, dichloromethane, acetonitrile or mixtures of solvents.The preferred solvent is dimethylformamide. Suitable bases are, inparticular, amine bases such as e.g. triethylamine ordiisopropylethylamine. Suitable coupling reagents may be for example1H-benzotriazol-1-yl-oxy-tripyrrolidino-phosphonium-hexafluorophosphate(PyBOP), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC),ethyl-(3-dimethylamino-propyl)-carbodiimide,O-(1H-benzo-triazol-1-yl)-N,N—N,N-tetramethyl-uroniumhexafluorophosphate (HBTU) or tetrafluoroborate (TBTU) or1H-benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (BOP). The use of TBTU is particularly preferred.The activation of the carboxyl group may also be carried out using acorresponding acid anhydride or acid chloride. The reaction is generallycarried out in a temperature range from −20° C. to the refluxtemperature of the solvent at normal pressure. It is particularlypreferable to use diisopropylethylamine as base and dimethylformamide assolvent.

The compounds of general formula (3-3), wherein R¹, R², R³ and R⁴ are ashereinbefore defined and R⁵ denotes a C₁₋₆-alkyl group, may besynthesised analogously to Scheme 3.

A compound of general formula (3-1), wherein R¹, R², R³ and R⁴ are ashereinbefore defined and R⁵ denotes a hydrogen atom, may be reacted witha compound of general formula (3-2), wherein alkyl denotes a C₁₋₆-alkylgroup and LG denotes a leaving group. The leaving group used may behalides, preferably bromides and iodides, —OSO₂CH₃, —OSO₂C₆H₄—CH₃, etc.,although this list is not restrictive. The use of iodides is mostparticularly preferred. The use of methyl iodides is most particularlypreferred. The reaction may be carried out in an inert solvent using anauxiliary base in a temperature range from 0° C. to the refluxtemperature of the solvent. Dimethylformamide, N-methylpyrrolidone,dimethylsulphoxide, acetonitrile or mixtures of solvents may be used asinert solvents. The preferred solvent is dimethylsulphoxide. Suitableauxiliary bases may be alkali metal carbonates such as potassiumcarbonate, sodium carbonate or caesium carbonate. The inert solvent usedmust be compatible with the base used. The use of caesium carbonate isparticularly preferred.

In some cases the end product may be further derivatised, e.g. bymanipulation of the substituents. These manipulations may be, interalia, those which are generally known to the skilled man, such asoxidation, reduction, alkylation, acylation and hydrolysis, but need notbe restricted to the above.

The new compounds of general formulae Ia and Ib according to theinvention may contain one or more chiral centres. If for example thereare two chiral centres present, the compounds may occur in the form oftwo diastereomeric pairs of antipodes. The invention includes theindividual isomers as well as the mixtures thereof.

The diastereomers may be separated on the basis of their differentphysico-chemical properties, e.g. by fractional crystallisation fromsuitable solvents, by high pressure liquid or column chromatography,using chiral or preferably non-chiral stationary phases.

Racemates covered by general formulae Ia and Ib may be separated forexample by HPLC on suitable chiral stationary phases (e.g. Chiral AGP,Chiralpak AD). Racemates which contain a basic or acidic function canalso be separated via the diastereomeric, optically active salts whichare produced on reacting with an optically active acid, for example (+)or (−)-tartaric acid, (+) or (−)-diacetyl tartaric acid, (+) or(−)-monomethyl tartrate or (+) or (−)-camphorsulphonic acid, or anoptically active base, for example with (R)-(+)-1-phenylethylamine,(S)-(−)-1-phenylethylamine or (S)-brucine.

According to a conventional method of separating isomers, the racemateof a compound of general formulae Ia and Ib is reacted with one of theabovementioned optically active acids or bases in equimolar amounts in asolvent and the resulting crystalline, diastereomeric, optically activesalts thereof are separated using their different solubilities. Thisreaction may be carried out in any type of solvent provided that it issufficiently different in terms of the solubility of the salts.Preferably, methanol, ethanol or mixtures thereof, for example in aratio by volume of 50:50, are used. Then each of the optically activesalts is dissolved in water, carefully neutralised with a base such assodium-carbonate or potassium carbonate, or with a suitable acid, e.g.with dilute hydrochloric acid or aqueous methanesulphonic acid, and inthis way the corresponding free compound is obtained in the (+) or (−)form.

The (R) or (S) enantiomer alone or a mixture of two optically activediastereomeric compounds covered by general formulae Ia and Ib may alsobe obtained by performing the syntheses described above with a suitablereaction component in the (R) or (S) configuration.

The new compounds of general formulae Ia and Ib and the physiologicallyacceptable salts thereof have valuable pharmacological properties, basedon their selective CGRP-antagonistic properties. The invention furtherrelates to pharmaceutical compositions containing these compounds, theiruse and the preparation thereof.

The new compounds mentioned above and the physiologically acceptablesalts thereof have CGRP-antagonistic properties and exhibit goodaffinities in CGRP receptor binding studies. The compounds displayCGRP-antagonistic properties in the pharmacological test systemsdescribed hereinafter.

The following experiments were carried out to demonstrate the affinityof the above-mentioned compounds for human CGRP-receptors and theirantagonistic properties:

A. Binding Studies with SK-N-MC Cells (Expressing the Human CGRPReceptor)

SK-N-MC membranes (˜20 μg protein) are incubated for 180 minutes atambient temperature with 50 pM ¹²⁵I-iodotyrosyl-Calcitonin-Gene-RelatedPeptide and increasing concentrations of the test substances in a totalvolume of 250 it (assay buffer: 10 mM tris, 50 mM NaCl, 5 mM MgCl₂, 1 mMEDTA, pH=7.4). The incubation is ended by rapid filtration throughGF/B-glass fibre filters treated with polyethyleneimine (0.1%) using acell harvester. The protein-bound radioactivity is measured using agamma counter. Non-specific binding is defined as the boundradioactivity after the presence of 1 μM BIBN4096BS during incubation.

The concentration binding curves are analysed using computer-aidednon-linear curve fitting.

The compounds mentioned hereinbefore show K_(i) values ≦50 μm in thetest described.

B. CGRP Antagonism in SK-N-MC Cells

SK-N-MC cells (˜1000 cells per well) are incubated for 30 minutes in thepresence of increasing concentrations of CGRP and differentconcentrations of the test substance.

The cAMP contents of the samples are determined using an AlphaScreencAMP assay kit (Perkin Elmer) and the pA₂ values of antagonisticallyacting substances are determined graphically.

The compounds according to the invention exhibit CGRP-antagonisticproperties in the in vitro test model described, in a dosage rangebetween 10⁻¹² and 10⁻⁴ M.

To demonstrate that the compounds of general formulae Ia and Ib exhibitgood to very good CGRP-antagonistic activities with different structuralelements, the following Table gives the K_(i) values obtained accordingto the test procedure described above. It should be noted that thecompounds were selected for their different structural elements and notin order to emphasise specific compounds:

Example K_(i) [nM] (2) 480 (3) 8.4 (4) 3.8

Indications

In view of their pharmacological properties the compounds according tothe invention and the salts thereof with physiologically acceptableacids are thus suitable for the acute and prophylactic treatment ofheadaches, particularly migraine or cluster headaches and tensionheadaches. Moreover, the compounds according to the invention also havea positive effect on the following diseases: non-insulin-dependentdiabetes mellitus (“NIDDM”), cardiovascular diseases, morphinetolerance, diarrhoea caused by clostridium toxin, skin diseases,particularly thermal and radiation-induced skin damage includingsunburn, lichen, pruritis, pruritic toxidermies and severe itching,inflammatory diseases, e.g. inflammatory diseases of the joints(osteoarthritis, rheumatoid arthritis, neurogenic arthritis),generalised soft-tissue rheumatism (fibromyalgia), neurogenicinflammation of the oral mucosa, inflammatory lung diseases, allergicrhinitis, asthma, COPD, diseases accompanied by excessive vasodilatationand resultant reduced blood supply to the tissues, e.g. shock andsepsis, chronic pain, e.g. diabetic neuropathies, neuropathies inducedby chemotherapy, HIV-induced neuropathies, postherpetic neuropathies,neuropathies induced by tissue trauma, trigeminal neuralgias,temporomandibular dysfunctions, CRPS (complex regional pain syndrome),back pain, and visceral complaints, such as e.g. irritable bowelsyndrome (IBS) and inflammatory bowel syndrome. In addition, thecompounds according to the invention have a general pain-relievingeffect. The symptoms of menopausal hot flushes caused by vasodilatationand increased blood flow in oestrogen-deficient women andhormone-treated patients with prostate carcinoma and castrated men arefavourably affected by the CGRP antagonists of the present applicationin a preventive and acute-therapeutic capacity, this therapeuticapproach being distinguished from hormone replacement by the absence ofside effects.

Preferably, the compounds according to the invention are suitable forthe acute and prophylactic treatment of migraine and cluster headaches,for the treatment of irritable bowel syndrome (IBS) and for thepreventive and acute-therapeutic treatment of hot flushes inoestrogen-deficient women.

The dosage required to achieve a corresponding effect is conveniently0.0001 to 3 mg/kg of body weight, preferably 0.01 to 1 mg/kg of bodyweight, when administered intravenously or subcutaneously, and 0.01 to10 mg/kg of body weight, preferably 0.1 to 10 mg/kg of body weight whenadministered orally, nasally or by inhalation, 1 to 3× a day in eachcase.

If the treatment with CGRP antagonists and/or CGRP release inhibitors isgiven as a supplement to conventional hormone replacement, it isadvisable to reduce the doses specified above, in which case the dosagemay be from ⅕ of the lower limits mentioned above up to 1/1 of the upperlimits specified.

The invention further relates to the use of the compounds according tothe invention as valuable adjuvants for the production and purification(by affinity chromatography) of antibodies as well as in RIA and ELISAassays, after suitable radioactive labelling, for example by tritiationof suitable precursors, for example by catalytic hydrogenation withtritium or replacing halogen atoms with tritium, and as a diagnostic oranalytical adjuvant in neurotransmitter research.

Combinations

Categories of active substance which may be used in combination includee.g. antiemetics, prokinetics, neuroleptics, antidepressants, neurokininantagonists, anticonvulsants, histamine-H1-receptor antagonists,β-blockers, α-agonists and α-antagonists, ergot alkaloids, mildanalgesics, non-steroidal antiphlogistics, corticosteroids, calciumantagonists, 5-HT_(1B/1D)-agonists or other anti-migraine agents whichmay be formulated together with one or more inert conventional carriersand/or diluents, e.g. with corn starch, lactose, glucose,microcrystalline cellulose, magnesium stearate, polyvinyl pyrrolidone,citric acid, tartaric acid, water, water/ethanol, water/glycerol,water/sorbitol, water/polyethylene glycol, propylene glycol,cetylstearyl alcohol, carboxymethylcellulose or fatty substances such ashard fat or suitable mixtures thereof, into conventional galenicpreparations such as plain or coated tablets, capsules, powders,suspensions, solutions, metered dose aerosols or suppositories.

Thus other active substances which may be used for the combinationsmentioned above include for example the non-steroidal antiinflammatoriesaceclofenac, acemetacin, acetyl-salicylic acid, acetaminophen(paracetamol), azathioprine, diclofenac, diflunisal, fenbufen,fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen,leflunomide, lornoxicam, mefenamic acid, naproxen, phenylbutazone,piroxicam, sulphasalazine, zomepirac or the pharmaceutically acceptablesalts thereof as well as meloxicam and other selective COX2-inhibitors,such as for example rofecoxib, valdecoxib, parecoxib, etoricoxib andcelecoxib, as well as substances that inhibit earlier or later stages ofprostaglandin synthesis or prostaglandin receptor antagonists such ase.g. EP2-receptor antagonists and IP-receptor antagonists.

It is also possible to use ergotamine, dihydroergotamine,metoclopramide, domperidone, diphenhydramine, cyclizine, promethazine,chlorpromazine, vigabatrin, timolol, isometheptene, pizotifen, botox,gabapentin, pregabalin, duloxetine, topiramate, riboflavin, montelukast,lisinopril, micardis, prochloroperazine, dexamethasone, flunarizine,dextropropoxyphene, meperidine, metoprolol, propranolol, nadolol,atenolol, clonidine, indoramin, carbamazepine, phenyloin, valproate,amitryptiline, imipramine, venlafaxine, lidocaine or diltiazem and other5-HT_(1B/1D)-agonists such as, for example, almotriptan, avitriptan,eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan andzolmitriptan.

Furthermore, CGRP antagonists with vanilloid receptor antagonists, suchas e.g. VR-1 antagonists, glutamate receptor antagonists, such as e.g.MGlu5 receptor antagonists, mGlu1 receptor antagonists, iGlu5 receptorantagonists, AMPA receptor antagonists, purine receptor blockers, suchas e.g. P2X3 antagonists, NO-synthase inhibitors, such as e.g. INOSinhibitors, calcium channel blockers, such as e.g. PQ-type blockers,N-type blockers, potassium channel openers, such as e.g. KCNQ channelopeners, sodium channel blockers, such as e.g. PN3 channel blockers,NMDA receptor antagonists, acid-sensing ion channel antagonists, such ase.g. ASIC3 antagonists, bradykinin receptor antagonists such as e.g. B1receptor antagonists, cannabinoid receptor agonists, such as e.g. CB2agonists, CB1 agonists, somatostatin receptor agonists, such as e.g.Sst2 receptor agonists may be added.

The dosage of these active substances is expediently ⅕ of the lowestusually recommended dose to 1/1 of the normally recommended dose, i.e.for example 20 to 100 mg of sumatriptan.

Formulations

The compounds prepared according to the invention may be administeredeither on their own or optionally in combination with other activesubstances for the treatment of migraine by intravenous, subcutaneous,intramuscular, intraarticular, intrarectal, intranasal route, byinhalation, topically, transdermally or orally, while aerosolformulations are particularly suitable for inhalation. The combinationsmay be administered either simultaneously or sequentially.

Suitable forms for administration are for example tablets, capsules,solutions, syrups, emulsions or inhalable powders or aerosols. Thecontent of the pharmaceutically effective compound(s) in each caseshould be in the range from 0.1 to 90 wt. %, preferably 0.5 to 50 wt. %of the total composition, i.e. In amounts which are sufficient toachieve the dosage range specified hereinafter.

The preparations may be administered orally in the form of a tablet, asa powder, as a powder in a capsule (e.g. a hard gelatine capsule), as asolution or suspension. When administered by inhalation the activesubstance combination may be given as a powder, as an aqueous oraqueous-ethanolic solution or using a propellant gas formulation.

Preferably, therefore, pharmaceutical formulations are characterised bythe content of one or more compounds of formulae Ia and Ib according tothe preferred embodiments above.

It is particularly preferable if the compounds of general formulae Iaand Ib are administered orally, and it is also particularly preferableif they are administered once or twice a day. Suitable tablets may beobtained, for example, by mixing the active substance(s) with knownexcipients, for example inert diluents such as calcium carbonate,calcium phosphate or lactose, disintegrants such as corn starch oralginic acid, binders such as starch or gelatine, lubricants such asmagnesium stearate or talc and/or agents for delaying release, such ascarboxymethyl cellulose, cellulose acetate phthalate, or polyvinylacetate. The tablets may also comprise several layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number of layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups containing the active substances or combinations thereofaccording to the invention may additionally contain a sweetener such assaccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. aflavouring such as vanillin or orange extract. They may also containsuspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Capsules containing one or more active substances or combinations ofactive substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriersprovided for this purpose, such as neutral fats or polyethyleneglycol orthe derivatives thereof.

Excipients which may be used include, for example, water,pharmaceutically acceptable organic solvents such as paraffins (e.g.petroleum fractions), vegetable oils (e.g. groundnut or sesame oil),mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carrierssuch as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk),synthetic mineral powders (e.g. highly dispersed silicic acid andsilicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers(e.g. lignin, spent sulphite liquors, methylcellulose, starch andpolyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc,stearic acid and sodium lauryl sulphate).

For oral administration the tablets may, of course, contain, apart fromthe abovementioned carriers, additives such as sodium citrate, calciumcarbonate and dicalcium phosphate together with various additives suchas starch, preferably potato starch, gelatine and the like. Moreover,lubricants such as magnesium stearate, sodium lauryl sulphate and talcmay be used at the same time for the tabletting process. In the case ofaqueous suspensions the active substances may be combined with variousflavour enhancers or colourings in addition to the excipients mentionedabove.

It is also preferred if the compounds of general formulae Ia and Ib areadministered by inhalation, particularly preferably if they areadministered once or twice a day. For this purpose, the compounds ofgeneral formulae Ia and Ib have to be made available in forms suitablefor inhalation. Inhalable preparations include inhalable powders,propellant-containing metered-dose aerosols or propellant-free inhalablesolutions, which are optionally present in admixture with conventionalphysiologically acceptable excipients.

Within the scope of the present invention, the term propellant-freeinhalable solutions also includes concentrates or sterile ready-to-useinhalable solutions. The preparations which may be used according to theinvention are described in more detail in the next part of thespecification.

EXPERIMENTAL SECTION

As a rule IR, ¹H-NMR and/or mass spectra have been obtained for thecompounds prepared. Unless stated otherwise, R_(f) values are determinedusing ready-made TLC silica gel plates 60 F254 (E. Merck, Darmstadt,Item no. 1.05714) without chamber saturation.

The ratios given for the eluants relate to units by volume of theparticular solvents. The units by volume given for NH₃ relate to aconcentrated solution of NH₃ in water.

Eluant Systems Used for TLC:

-   -   eluant A: DCM/cyclohexane/MeOH/NH₄OH=70/15/15/2    -   eluant B: petroleum ether/ethyl acetate=2/1

Unless stated otherwise, the acid, base and salt solutions used inworking up the reaction solutions are aqueous systems of the specifiedconcentrations. Silica gel made by Millipore (MATREX™, 35-70 μm) is usedfor chromatographic purifications.

The HPLC data provided are measured under the parameters listed belowand using the columns mentioned:

Columns Used:

(column temperature: 30° C.; injection volume: 5 μL; detection at 254nm)

S1 Zorbax column (Agilent Technologies), SB (Stable Bond) C18; 3.5 μm;4.6 × 75 mm S2 Waters Sunfire, SB (Stable Bond) C18; 3.5 μm; 4.6 × 75 mmS3 Agilent Bonus C18; 5 μm, 4.6 × 75 mm S4 Zorbax column (AgilentTechnologies), SB (Stable Bond) C18; 1.8 μm; 3.0 × 30 mm S5 Zorbaxcolumn (Agilent Technologies), SB (Stable Bond) C18; 5 μm; 4.6 × 75 mmS6 Waters Symmetry C18; 3.5 μm; 4.6 × 75 mm S7 Waters XBridge C18; 3.5μm; 4.6 × 75 mm (basic column)

Solvents Used:

-   -   for the columns S1 to S6 (acid conditions) the following        solvents were used:        solvent A: water (with 0.1% formic acid)        solvent B: acetonitrile (with 0.1% formic acid)    -   for the column S7 (basic conditions) the following solvents were        used:        solvent A: water (with 0.1% NH₄OH)        solvent B: acetonitrile (with 0.1% NH₄OH)        (the percentages given relate to the total volume)

Gradients:

gradient time (flow) [min] % A % B G1 0.0 95 5 (0.8 mL/min) 8.0 50 509.0 10 90 10.0 10 90 11.0 95 5 G2 0.00 95 5 (1.6 mL/min) 0.10 95 5 1.755 95 1.90 5 95 1.95 95 5 2.00 95 5 G3 0.00 95 5 (1.6 mL/min) 4.50 10 905.00 10 90 5.50 95 5 G4 0.00 95 5 (1.6 mL/min) 4.00 50 50 4.50 10 905.00 10 90 5.50 95 5 G5 0.00 90 10 (1.6 mL/min) 4.50 10 90 5.50 10 90 G60.0 95 5 (0.8 mL/min) 9.0 10 90 10.0 10 90 11.0 95 5 G7 0.00 95 5 (1.6mL/min) 2.00 50 50 2.25 10 90 2.50 10 90 2.75 95 5

Methods:

method column gradient method A S1 G4 method B S2 G4 method C S4 G2method D S6 G4 method E S1 G3 method F S3 G3 method G S5 G4 method H S1G5 method K S2 G3 method L S1 G2 method M S7 G3 method N S2 G1 method OS4 G7

In preparative HPLC purifications, the products are collected eitherunder mass control or by UV detection. The fractions containing productare combined and freeze-dried. The following columns may be used forpreparative HPLC separations:

S8 Agilent Zorbax SB C18, 50 × 150 mm, 5 μm S9 Agilent Zorbax StableBond, 50 × 140 mm, 7 μm S10 Waters Sunfire C18, 30 × 100 mm, 5 μm S11Waters Symmetry 50 × 140 mm, 7 μm S12 Agilent Zorbax Stable Bond C18, 30× 100 mm, 5 μm,The following solvent systems may be used for the preparative HPLCseparation:

-   -   solvent A: water (with 0.1% formic acid)    -   solvent B: acetonitrile (with 0.1% formic acid)    -   solvent A: water (with 0.15% formic acid)    -   solvent B: acetonitrile (with 0.15% formic acid)    -   solvent A: water (with 0.3% formic acid)    -   solvent B: acetonitrile    -   solvent A: water (with 0.3% formic acid)    -   solvent B: acetonitrile (with 0.3% formic acid)    -   solvent A: water (with 0.1% NH₄OH)    -   solvent B: acetonitrile (with 0.1% NH₄OH)

The percentages given relate in each case to the total volume.

In the absence of any more information regarding the configuration, itis unclear whether there are pure enantiomers involved or whetherpartial or even total racemisation has taken place.

The following abbreviations are used in the test descriptions:

-   AcOH acetic acid-   BINAP 2,2′-bis-(diphenylphosphino)-1,1′-binaphthyl-   BOC tert.-butyloxycarbonyl-   CAD circulating air dryer-   CDI 1,1′-carbonyldiimidazole-   conc. concentrated-   Cyc cyclohexane-   DCM dichloromethane-   DIPE diisopropylether-   DIPEA diisopropylethylamine-   DMF N,N-dimethylformamide-   dppf 1,1′-bis-(diphenylphosphino)ferrocene-   of th. of theory-   d-water deionised water-   EI electron jet ionisation (in MS)-   eq equivalents-   ESI electrospray ionisation (in MS)-   EtOAc ethyl acetate-   EtOH ethanol-   h hour(s)-   HCl hydrogen chloride-   HPLC High Performance Liquid Chromatography-   HPLC-MS HPLC coupled mass spectrometry-   i.vac. in vacuo (under vacuum)-   M molar-   mmol millimol-   mL millilitre-   μL microlitre-   MeOH methanol-   MS mass spectrometry-   MW molecular weight [g/mol]-   NaOAc sodium acetate-   NaOH sodium hydroxide-   NH₄OH ammonium hydroxide (aqueous ammonia solution, 30%)-   NMP N-methylpyrrolidine-   PE petroleum ether-   quant. quantitative-   R_(f) retention factor (in TLC)-   R_(t) retention time (in HPLC)-   RT ambient temperature-   TBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    tetrafluoroborate-   TEA triethylamine-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TLC thin layer chromatography-   XantPhos 4,5-bis(diphenylphosphino)-9.9-dimethylxanthene-   XPhos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

Preparation of the Starting Compounds Intermediate 1a1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one-dihydrochloride

This compound and its precursors were synthesised as described inInternational Application WO 2005/013894.

ESI-MS: m/z=219 (M+H)⁺

R_(f): 0.11 (silica gel, DCM/MeOH/NH₄OH=80:20:2)

Intermediate 1b 1-Piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one

Step 1: Benzyl 4-(2-chloro-pyridin-3-yl-amino)-piperidine-1-carboxylate

560 mL (7.25 mol) TFA were added dropwise at about 15° C. to 930 g (3.99mol) of N-benzyloxycarbonyl-4-piperidone and 466 g (3.63 mol) of2-chloro-3-aminopyridine in 9.5 L of isopropyl acetate. 922 g (4.35 mol)of sodium triacetoxyborohydride were added batchwise. The mixture wasstirred until the reaction was complete. At RT the reaction mixture wascombined with 860 mL sodium hydroxide solution (2 mol/L). The organicphase was separated off, washed with 5 L water and concentrated byevaporation.

Yield: 1250 g (crude, quant.)

ESI-MS: m/z=346 (M+H)⁺

Step 2: Benzyl4-[1-(2-chloro-pyridin-3-yl)-ureido]-piperidine-1-carboxylate

530 mL (6.1 mol) chlorosulphonyl isocyanate were placed in 6 L THF andcooled to −15° C. A solution of 1.25 kg (3.63 mol) benzyl4-(2-chloro-pyridin-3-yl-amino)-piperidine-1-carboxylate in 7 L of THFwas then added to this mixture within one hour in such a way that thetemperature of the reaction mixture did not exceed −7° C. The mixturewas stirred for 90 minutes at about −8° C. and then 700 mL of water wereadded dropwise within 30 minutes. The mixture was stirred for 30 minutesat about 10° C. and then 8.1 L sodium hydroxide solution (2 mol/L) wereslowly added. The reaction mixture was then heated to 50° C. and thephases were separated. The organic phase was washed with 2 L of water.Then 10 L of solvent were distilled off from the organic phase, 15 L ofbutyl acetate were added to the residue and from this another 8 L weredistilled off again. The product was crystallised by slow cooling to 0°C. The precipitate was suction filtered, washed with 2 L butyl acetateand dried at 40° C.

Yield: 1108 g (79% of th.)

ESI-MS: m/z=389/391(M+H)⁺

Step 3: Benzyl4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidine-1-carboxylate

1108 g (2.85 mol) of benzyl4-[1-(2-chloro-pyridin-3-yl)-ureido]-piperidine-1-carboxylate wererefluxed with 720 g (8.57 mol) sodium hydrogen carbonate in 14.5 L oftert-amyl alcohol. 3 L of solvent were distilled off. The reactionmixture was cooled to 35° C. and mixed with 11 mL water. Then 13 g(0.058 mol) palladium acetate and 49 g (0.115 mol)1,4-bis-(diphenylphosphino)-butane (DPPB) were added and the mixture washeated to reflux temperature. It was stirred at 100° C. until thereaction was complete, then cooled to RT and 7.5 L of water were added.The organic phase was separated off, washed with 5 L water and thenevaporated down. Two lots of 3 L of isopropyl acetate were added to theoily residue and it was distilled off. Then the residue was dissolvedhot in 7 L of isopropyl acetate and the mixture was slowly cooled toambient temperature. The solid that crystallised out was suctionfiltered, washed with 2 L isopropyl acetate and tert.-butyl-methyletherand dried at 50° C.

Yield: 690 g (69% of th.)

ESI-MS: m/z=353 (M+H)⁺

Step 4: 1-Piperidin-4-yl-1,3-dihydro-imidazol-[4,5-b]pyridin-2-one

690 g (1.96 mol) benzyl4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidine-1-carboxylatewere dissolved in 5.4 L methanol and hydrogenated at 60° C. with theaddition of 46 g Pd/C (10%; 6.6% by weight) at a hydrogen pressure of 60psi until the uptake of hydrogen was complete. The catalyst was filteredoff. 4 L of methanol were distilled off from the filtrate. 2 L ofmethylcyclohexane were added and another 1.5 L of solvent were distilledoff. The suspension thus obtained was suction filtered, the residue waswashed with methylcyclohexane and dried at 40° C.

Yield: 446 g (100% of th.)

ESI-MS: m/z=219 (M+H)⁺

Intermediate 27-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one

Step 1: (5-methoxy-2-nitrophenyl)-acetonitrile

24.0 g (214 mmol) potassium-tert-butoxide in 100 mL DMF were slowlyadded dropwise to a solution of 13.2 g (86.0 mmol) 4-nitroanisole and18.0 g (107 mmol) of 4-chlorophenoxy-acetonitrile in 50 mL DMF. Thereaction mixture was stirred for 30 min at −10° C. and then poured into300 g of a 1:1 mixture of conc. HCl and ice. After extraction with EtOActhe organic phase was washed with water, dried and evaporated down i.vac. The residue was treated with a 1:1 mixture PE/EtOAc and the productthat crystallised out was suction filtered. After washing with a 1:1mixture of petroleum ether/EtOAc the crystals were dried in the air.

Yield: 6.5 g (39% of theoretical)

ESI-MS: m/z=210 (M+NH₄)⁺

R_(f): 0.45 (silica gel; PE/EtOAc=1:1)

Step 2: 2-(5-methoxy-2-nitrophenyl)-ethylamine

Under a nitrogen atmosphere, 200 mL (200 mmol) of a 1M borane in THFsolution were slowly added dropwise at RT to 12.6 g (65.7 mmol)(5-methoxy-2-nitrophenyl)-acetonitrile in 380 mL THF. The reactionmixture was refluxed for 2 h. After cooling 30 mL methanol were addeddropwise within 20 min. During this time the temperature was maintainedat 10° C. to 20° C. with an ice bath. The reaction mixture was left for30 min at RT with stirring and then within 30 min 45 mL of a 2M aqueousHCl solution were added dropwise thereto. The reaction mixture wasconcentrated by rotary evaporation i. vac. The residue was diluted withwater to approx. 200 mL and extracted with 200 mL EtOAc. The aqueousphase was made alkaline with a 15% (w/v) aqueous potassium carbonatesolution and continuously extracted overnight with diethyl ether using arotary perforator according to Ludwig (Messrs Normag). The organicextract was evaporated to dryness by rotary evaporation.

Yield: 9.98 g (77% of theoretical)

ESI-MS: m/z=197 (M+H)⁺

R_(t) (HPLC): 2.1 min (method E)

Step 3:(1-benzylpiperidin-4-yl)-[2-(5-methoxy-2-nitrophenyl)-ethyl]-amine

Under a nitrogen atmosphere a mixture of 9.98 g (50.9 mmol)2-(5-methoxy-2-nitrophenyl)-ethylamine, 9.80 mL (54.9 mmol)N-benzylpiperidone and 6.30 mL (114 mmol) acetic acid in 270 mLdichloromethane was cooled to 0° C. in an ice bath. At this temperature14.2 g (67.0 mmol) sodium triacetoxyborohydride were added batchwisewithin 20 min. The reaction mixture was left for a further 4 h at 0° C.and warmed up to RT overnight. Then the mixture was combined with 400 mLof a 15% (w/v) aqueous potassium carbonate solution and stirred for 1 hat RT. The organic phase was separated off, dried and concentrated byrotary evaporation.

Yield: 18.8 g (quantitative)

ESI-MS: m/z=370 (M+H)⁺

R_(t) (HPLC): 1.9 min (method E)

Step 4:[2-(2-amino-5-methoxyphenyl)-ethyl]-(1-benzylpiperidin-4-yl)-amine

26.0 g (70.3 mmol)(1-benzylpiperidin-4-yl)-[2-(5-methoxy-2-nitrophenyl)-ethyl]-amine werehydrogenated with 5.00 g (2.45 mmol) rhodium charcoal (5%, moistenedwith water) in 350 mL methanol in a 3 bar hydrogen atmosphere for 3 h atRT. The catalyst was removed by suction filtering and the solution wasconcentrated by rotary evaporation. The residue was immediately furtherreacted without any further purification.

Yield: 23.9 g (quantitative)

R_(t) (HPLC): 0.99 min (method A)

Step 5:3-(1-benzylpiperidin-4-yl)-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one

35.0 g (216 mmol) N,N′-carbonyldiimidazole were added to 23.9 g (70.3mmol) [2-(2-amino-5-methoxyphenyl)-ethyl]-(1-benzylpiperidin-4-yl)-aminein 175 mL DMF and the mixture was stirred for 2 h at 100° C. Thereaction mixture was poured onto approx. 1 kg ice water and stirredovernight. The precipitated product was suction filtered, washed withwater and dried. The residue was stirred with DIPE and suction filtered.The solid product was washed with DIPE and dried.

Yield: 21.6 g (84% of theoretical)

ESI-MS: m/z=366 (M+H)⁺

R_(t) (HPLC): 2.12 min (method E)

Step 6:7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one

A mixture of 21.6 g (59.2 mmol)3-(1-benzylpiperidin-4-yl)-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-oneand 2.5 g palladium on charcoal (10%) in 300 mL methanol washydrogenated in a 3 bar hydrogen atmosphere at 50° C. until the reactionwas complete. The catalyst was removed by suction filtering and themother liquor was concentrated by rotary evaporation. The residue wastriturated with DIPE, suction filtered, washed with DIPE and dried.

Yield: 13.2 g (81% of theoretical)

ESI-MS: m/z=276 (M+H)⁺

R_(t) (HPLC): 0.73 min (method L)

Intermediate 3(2-chloro-6-methoxypyridin-4-yl)-(5-fluoro-2,3-dihydroindol-1-yl)-methanone

0.965 g (3.00 mmol) TBTU was added at RT to 0.500 g (2.67 mmol)2-chloro-6-methoxyisonicotinic acid, 0.366 g (2.67 mmol)5-fluoroindoline and 0.421 mL (3.00 mmol) triethylamine in 10.0 mL DMF.The mixture was stirred for 2 h at RT and then purified by preparativeHPLC. The fractions containing the product were combined and evaporateddown i. vac.

Yield: 0.700 g (86% of theoretical)

ESI-MS: m/z=307/309 (M+H)⁺ (CI)

R_(t) (HPLC): 1.60 min (method C)

Intermediate 4 5-fluoro-3,3-dimethyl-2,3-dihydro-1H-indole

Step 1: 1-acetyl-5-fluoro-1,3-dihydroindol-2-one

At 170° C. 3.0 g (20 mmol) 5-fluoroindolinone were stirred in 10 mL (98mmol) acetic anhydride for 3 h. After cooling to RT the mixture waspoured onto 200 mL ice water, the precipitated substance was suctionfiltered and washed with 100 mL water. The solid was recrystallised fromwater and ethanol. The precipitated product was suction filtered, washedwith water and dried i. vac.

Yield: 2.4 g (63% of theory)

ESI-MS: m/z=192 (M+H)⁺

R_(t) (HPLC): 1.2 min (method C)

Step 2: 1-acetyl-5-fluoro-3,3-dimethyl-1,3-dihydroindol-2-one

At 0° C. to 5° C., 1.14 g (26.0 mmol) sodium hydride (55% in mineraloil) was added batchwise under an argon atmosphere to 2.40 g (12.4 mmol)1-acetyl-5-fluoro-1,3-dihydroindol-2-one in 30 mL DMF and the mixturewas stirred for 1 h. Then 1.91 mL (31.0 mmol) methyl iodide were addeddropwise and the mixture was stirred overnight at RT. The reactionmixture was poured onto water and the precipitated substance was suctionfiltered. The solid was washed with water and dried i. vac.

Yield: 2.1 g (76% of theory)

ESI-MS: m/z=222 (M+H)⁺

R_(t) (HPLC): 1.48 min (method C)

Step 3: 5-fluoro-3,3-dimethyl-1,3-dihydroindol-2-one

2.10 g (9.49 mmol)1-acetyl-5-fluoro-3,3-dimethyl-1,3-dihydro-indol-2-one in 20 mLisopropanol were refluxed with 50 mL of a 6M aqueous HCl solution for 1h. After cooling the isopropanol was eliminated i. vac. The residue wasdiluted with water and cooled with ice. The precipitated substance wassuction filtered and washed with water. The solid was dried i. vac.

Yield: 1.40 g (82% of theory)

ESI-MS: m/z=180 (M+H)⁺

R_(t) (HPLC): 1.14 min (method C)

Step 4: 5-fluoro-3,3-dimethyl-2,3-dihydro-1H-indole

Under an argon atmosphere a solution of 9.30 mL (9.30 mmol) of a 1Msolution of lithium aluminium hydride in THF and 10 mL THF was slowlyadded dropwise to 1.40 g (7.81 mmol)5-fluoro-3,3-dimethyl-1,3-dihydroindol-2-one in 50 mL THF. Then thereaction mixture was heated to 70° C. for 1 h. After cooling 2 mL waterwere added. The solution was dried on sodium sulphate and filtered off.The solvent was eliminated i. vac.

Yield: 1.30 g (quant.)

ESI-MS: m/z=166 (M+H)⁺

R_(t) (HPLC): 0.75 min (method C)

Intermediate 5(2-chloro-6-methoxypyridin-4-yl)-(5-fluoro-3,3-dimethyl-2,3-dihydroindol-1-yl)-methanone

This compound was obtained analogously to(2-chloro-6-methoxypyridin-4-yl)-(5-fluoro-2,3-dihydroindol-1-yl)-methanonefrom 0.500 g (2.67 mmol) 2-chloro-6-methoxyisonicotinic acid, 0.439 g(2.66 mmol) 5-fluoro-3,3-dimethyl-2,3-dihydro-1H-indole and 0.421 mL(3.00 mmol) triethylamine in 10.0 mL DMF.

Yield: 0.600 g (67% of theory)

ESI-MS: m/z=335/337 (M+H)⁺ (CI)

R_(t) (HPLC): 1.73 min (method C)

Intermediate 61-[4′-(5-fluoro-2,3-dihydroindole-1-carbonyl)-6′-methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-1,3-dihydroimidazo[4,5-b]pyridin-2-one

A mixture of 0.361 g (1.24 mmol)1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one dihydrochloride,0.380 mg (1.24 mmol)(2-chloro-6-methoxypyridin-4-yl)-(5-fluoro-2,3-dihydroindol-1-yl)-methanoneand 514 mg (3.72 mmol) potassium carbonate in 3.0 mL NMP was stirred for8 h at 130° C. After cooling the reaction mixture to RT the precipitateformed was filtered off and purified by preparative HPLC. The fractionscontaining the product were combined and evaporated down i. vac.

Yield: 0.090 g (15% of theoretical)

ESI-MS: m/z=489 (M+H)⁺

R_(t) (HPLC): 1.50 min (method C)

Intermediate 73-[4′-(5-fluoro-2,3-dihydroindole-1-carbonyl)-6′-methoxy-3,4,5,6-tetrahydro-2H-1,2′-bipyridinyl-4-yl]-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one

A mixture of 0.633 g (2.30 mmol)7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one,0.700 mg (2.28 mmol)(2-chloro-6-methoxypyridin-4-yl)-(5-fluoro-2,3-dihydroindol-1-yl)-methanoneand 954 mg (6.90 mmol) potassium carbonate in 5.0 mL NMP was stirred for8 h at 130° C. After cooling the reaction mixture to RT the precipitateformed was filtered off and purified by preparative HPLC. The fractionscontaining the product were combined and evaporated down i. vac. Theresidue obtained was digested in DMF and the product remaining as asolid was suction filtered and dried i. vac. The mother liquor was againpurified by preparative HPLC, the fractions containing product werecombined and evaporated down i. vac. The residue was triturated withethanol, the solid product was suction filtered and dried i. vac.

Yield: 0.490 g (39% of theoretical)

ESI-MS: m/z=546 (M+H)⁺

R_(t) (HPLC): 1.50 min (method C)

Intermediate 81-[4′-(5-fluoro-3,3-dimethyl-2,3-dihydroindole-1-carbonyl)-6′-methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-1,3-dihydroimidazo[4,5-b]pyridin-2-one

This compound was obtained analogously to1-[4′-(5-fluoro-2,3-dihydroindole-1-carbonyl)-6′-methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-1,3-dihydroimidazo[4,5-b]pyridin-2-onefrom 262 mg (0.900 mmol)1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one dihydrochloride,300 mg (0.90 mmol)(2-chloro-6-methoxypyridin-4-yl)-(5-fluoro-3,3-dimethyl-2,3-dihydroindol-1-yl)-methanoneand 373 mg (2.70 mmol) potassium carbonate in 3.0 mL NMP.

Yield: 40 mg (9% of theoretical)

ESI-MS: m/z=517 (M+H)⁺

R_(t) (HPLC): 1.62 min (method C)

Intermediate 91-[4′-(4,5-Difluoro-2,3-dihydro-indole-1-carbonyl)-6′-methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

Step 1:(2-Chloro-6-methoxy-pyridin-4-yl)-(4,5-difluoro-2,3-dihydro-indol-1-yl)-methanone

1.22 g (3.80 mmol) TBTU were added at RT to 0.685 g (3.65 mmol)2-chloro-6-methoxyisonicotinic acid, 0.700 g (3.65 mmol)4,5-fluoroindoline-dihydrochloride and 1.12 mL (8.00 mmol) triethylaminein 10.0 mL DMF. The mixture was stirred for 2 h at RT and then pouredonto 200 mL of potassium carbonate solution (aqueous, 7%). Theprecipitate formed was suction filtered, washed with water and dried i.vac.

Yield: 1.05 g (89% of th.)

ESI-MS: m/z=325/327 (M+H)⁺ (CI)

R_(t) (HPLC): 1.66 min (method C)

Step 2:1-[4′-(4,5-Difluoro-2,3-dihydro-indole-1-carbonyl)-6′-methoxy-3,4,5,6-tetra-hydro-2H-[1,2]bipyridinyl-4-yl]-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

0.982 g (4.50 mmol)1-Piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one and 500 mg (1.54mmol)(2-chloro-6-methoxy-pyridin-4-yl)-(4,5-difluoro-2,3-dihydro-indol-1-yl)-methanonein 3.0 mL NMP were stirred for 12 h at 130° C. After the reactionmixture had cooled to RT the precipitate formed was filtered off andpurified by preparative HPLC. The product-containing fractions werecombined and lyophilised.

Yield: 0.250 g (32% of th.)

ESI-MS: m/z=507 (M+H)⁺

R_(t) (HPLC): 1.59 min (method C)

Intermediate 101-[6′-(5-Fluoro-2,3-dihydro-indole-1-carbonyl)-2′-methoxy-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl]-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

Step 1:(4-Chloro-6-methoxy-pyridin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone

550 mg (2.93 mmol) 4-chloro-6-methoxy-pyridine-2-carboxylate, 411 mg(3.00 mmol) 5-fluoroindoline, 1.06 g (3.30 mmol) TBTU and 927 uL (6.60mmol) triethylamine in 5.00 mL DMF were stirred for 3 h at RT. Thereaction mixture was purified by HPLC. The product-containing fractionswere combined and evaporated down using the rotary evaporator.

Yield: 450 mg (50% of th.)

ESI-MS: m/z=307/309 (M+H)⁺ (CI)

R_(t) (HPLC): 1.7 min (method C)

Step 2:1-[6′-(5-Fluoro-2,3-dihydro-indole-1-carbonyl)-2′-methoxy-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl]-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

436 mg (2.00 mmol)1-Piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one and 200 mg(0.652 mmol) of(4-chloro-6-methoxy-pyridin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanonein 2 mL NMP were stirred overnight at 120° C. The reaction mixture waspurified by preparative HPLC. The product-containing fractions werecombined and evaporated down using the rotary evaporator.

Yield: 62 mg (20% of th.)

ESI-MS: m/z=487 (M−H)⁻

R_(t) (HPLC): 1.7 min (method C)

Preparation of the End Compounds Example 14′-(5-fluoro-2,3-dihydroindole-1-carbonyl)-4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H,1′H-[1,2′]bipyridinyl-6′-one

A well stirred mixture of 20 mg (0.041 mmol)1-[4′-(5-fluoro-2,3-dihydroindole-1-carbonyl)-6′-methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-1,3-dihydroimidazo[4,5-b]pyridin-2-oneand 100 mg (0.865 mmol) pyridine hydrochloride was kept in a melt for 7min using a hot air blower. After the reaction mixture had cooled it wasdissolved in DMF and purified by preparative HPLC. The fractionscontaining the product were combined and lyophilised.

Yield: 11 mg (57% of theoretical)

ESI-MS: m/z=476 (M+H)⁺

R_(t) (HPLC): 1.17 min (method C)

Example 24′-(5-fluoro-2,3-dihydroindole-1-carbonyl)-1′-methyl-4-(2-oxo-2,3-dihydroimidazo[4,5-b]-pyridin-1-yl)-3,4,5,6-tetrahydro-2H,1′H-[1,2′]bipyridinyl-6′-one

50 mg (0.11 mmol) of4′-(5-fluoro-2,3-dihydroindole-1-carbonyl)-4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H,1′H-[1,2′]bipyridinyl-6′-onewere placed in 0.50 mL DMSO at RT. To this were added 88 mg (0.27 mmol)caesium carbonate and the mixture was stirred for 15 min. Then asolution of 6.5 μL (0.11 mmol) methyl iodide in DMSO was added and themixture was stirred for 2 h at RT. More methyl iodide was added (3.3 μL,0.055 mmol) and the mixture was stirred for a further 2 h at RT. Thereaction mixture was purified by preparative HPLC. The fractionscontaining the product were combined and lyophilised.

Yield: 15 mg (29% of theoretical)

ESI-MS: m/z=489 (M+H)⁺

R_(t) (HPLC): 1.88 min (method O)

Example 33-[4′-(5-fluoro-2,3-dihydroindole-1-carbonyl)-6′-oxo-3,4,5,6,1′,6′-hexahydro-2H-1,2′-bipyridinyl-4-yl]-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one

This compound was obtained analogously to4′-(5-fluoro-2,3-dihydroindole-1-carbonyl)-4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H,1′H-[1,2′]bipyridinyl-6′-onefrom 415 mg (0.761 mmol)3-[4′-(5-fluoro-2,3-dihydroindole-1-carbonyl)-6′-methoxy-3,4,5,6-tetrahydro-2H-1,2′-bipyridinyl-4-yl]-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-oneand 1.50 g (13.0 mmol) pyridine hydrochloride.

Yield: 39 g (10% of theoretical)

ESI-MS: m/z=532 (M+H)⁺

R_(t) (HPLC): 4.80 min (method N)

Example 44′-(5-fluoro-3,3-dimethyl-2,3-dihydroindole-1-carbonyl)-4-(2-oxo-2,3-dihydroimidazo[4,5-b]-pyridin-1-yl)-3,4,5,6-tetrahydro-2H,1′H-[1,2′]bipyridinyl-6′-one

This compound was obtained analogously to4′-(5-fluoro-2,3-dihydroindole-1-carbonyl)-4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H,1′H-[1,2′]bipyridinyl-6′-onefrom 60 mg (0.12 mmol)1-[4′-(5-fluoro-3,3-dimethyl-2,3-dihydroindole-1-carbonyl)-6′-methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-1,3-dihydroimidazo[4,5-b]pyridin-2-oneand 300 mg (2.6 mmol) pyridine hydrochloride.

Yield: 20 mg (34% of theoretical)

ESI-MS: m/z=503 (M+H)⁺

R_(t) (HPLC): 1.17 min (method C)

Example 5 4′-(5-fluoro-3,3-dimethyl-2,3-dihydroindole-1-carbonyl)-1′-methyl-4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H,1′H-[1,2′]bipyridinyl-6′-one

This compound was obtained analogously to4′-(5-fluoro-2,3-dihydroindole-1-carbonyl)-1′-methyl-4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H,1′H-[1,2′]bipyridinyl-6′-onefrom 20 mg (0.040 mmol) of4′-(5-fluoro-3,3-dimethyl-2,3-dihydroindole-1-carbonyl)-4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H,1′H-[1,2′]bipyridinyl-6′-one,3.8 μL (0.060 mmol) methyl iodide and 33 mg (0.10 mmol) caesiumcarbonate in 0.50 mL DMSO.

Yield: 15 mg (73% of theoretical)

ESI-MS: m/z=517 (M+H)⁺

R_(t) (HPLC): 2.16 min (method C)

Example 64′-(4,5-Difluoro-2,3-dihydro-indole-1-carbonyl)-4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H,1′H-[1,2′]bipyridinyl-6′-one

A well stirred mixture of 100 mg (0.197 mmol)1-[4′-(4,5-difluoro-2,3-dihydro-indole-1-carbonyl)-6′-methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-1,3-dihydro-imidazo[4,5-b]pyridin-2-oneand 0.500 g (4.33 mmol) pyridine hydrochloride was kept in a melt for 7min using a hot air blower. After the reaction had cooled the mixturewas dissolved in DMF and purified by preparative HPLC. Theproduct-containing fractions were combined and lyophilised.

Yield: 56 mg (58% of th.)

ESI-MS: m/z=493 (M+H)⁺

R_(t) (HPLC): 1.27 min (method C)

Example 76′-(5-Fluoro-2,3-dihydro-indole-1-carbonyl)-4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-3,4,5,6-tetrahydro-2H,1′H-[1,4′]bipyridinyl-2′-one

A well stirred mixture of 40 mg (0.082 mmol)1-[6′-(5-fluoro-2,3-dihydro-indole-1-carbonyl)-2′-methoxy-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl]-1,3-dihydro-imidazo-[4,5-b]pyridin-2-oneand 0.020 g (1.7 mmol) pyridine hydrochloride was kept in a melt for 2min using a hot air blower. After the reaction had cooled the mixturewas dissolved in DMF and purified by preparative HPLC. Theproduct-containing fractions were combined and lyophilised.

Yield: 22 mg (57% of th.)

ESI-MS: m/z=475 (M+H)⁺

R_(t) (HPLC): 1.1 min (method C)

The following Examples describe the preparation of pharmaceuticalformulations that contain as active substance any desired compound ofgeneral formulae Ia and Ib:

Example I Capsules for Powder Inhalation Containing 1 mg of ActiveIngredient Composition: 1 Capsule for Powder Inhalation Contains:

active ingredient  1.0 mg lactose 20.0 mg hard gelatine capsules 50.0 mg71.0 mg

Method of Preparation:

The active ingredient is ground to the particle size required forinhaled substances. The ground active ingredient is homogeneously mixedwith the lactose. The mixture is transferred into hard gelatinecapsules.

Example II Inhalable Solution for Respimat® Containing 1 mg of ActiveIngredient Composition: 1 Puff Contains:

active ingredient 1.0 mg benzalkonium chloride 0.002 mg disodium edetate0.0075 mg purified water ad 15.0 μl

Method of Preparation:

The active ingredient and benzalkonium chloride are dissolved in waterand transferred into Respimat® cartridges.

Example III Inhalable Solution for Nebulisers Containing 1 mg of ActiveIngredient Composition: 1 Vial Contains:

active ingredient 0.1 g sodium chloride 0.18 g benzalkonium chloride0.002 g purified water ad 20.0 ml

Method of Preparation:

The active ingredient, sodium chloride and benzalkonium chloride aredissolved in water.

Example IV Propellant Gas-Operated Metered Dose Aerosol Containing 1 mgof Active Ingredient Composition: 1 Puff Contains:

active ingredient 1.0 mg lecithin 0.1% propellant gas ad 50.0 μl

Method of Preparation:

The micronised active ingredient is homogeneously suspended in themixture of lecithin and propellant gas. The suspension is transferredinto a pressurised container with a metering valve.

Example V Nasal Spray Containing 1 mg of Active Ingredient Composition:

active ingredient 1.0 mg sodium chloride 0.9 mg benzalkonium chloride0.025 mg disodium edetate 0.05 mg purified water ad 0.1 ml

Method of Preparation:

The active ingredient and the excipients are dissolved in water andtransferred into a suitable container.

Example VI Injectable Solution Containing 5 mg of Active Substance Per 5ml Composition:

active substance 5 mg glucose 250 mg human serum albumin 10 mgglycofurol 250 mg water for injections ad 5 ml

Preparation:

Glycofurol and glucose are dissolved in water for injections (WfI);human serum albumin is added; active ingredient is dissolved withheating; made up to specified volume with WfI; transferred into ampoulesunder nitrogen gas.

Example VII Injectable Solution Containing 100 mg of Active SubstancePer 20 ml Composition:

active substance 100 mg monopotassium dihydrogen phosphate = KH₂PO₄ 12mg disodium hydrogen phosphate = Na₂HPO₄*2H₂O 2 mg sodium chloride 180mg human serum albumin 50 mg Polysorbate 80 20 mg water for injectionsad 20 ml

Preparation:

Polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate anddisodium hydrogen phosphate are dissolved in water for injections (WfI);human serum albumin is added; active ingredient is dissolved withheating; made up to specified volume with WfI; transferred intoampoules.

Example VIII Lyophilisate Containing 10 mg of Active SubstanceComposition:

Active substance 10 mg Mannitol 300 mg human serum albumin 20 mg waterfor injections ad 2 ml

Preparation:

Mannitol is dissolved in water for injections (WfI); human serum albuminis added; active ingredient is dissolved with heating; made up tospecified volume with WfI; transferred into vials; freeze-dried.

Solvent for Lyophilisate:

Polysorbate 80 = Tween 80 20 mg mannitol 200 mg water for injections ad10 ml

Preparation:

Polysorbate 80 and mannitol are dissolved in water for injections (WfI);transferred into ampoules.

Example IX Tablets Containing 20 mg of Active Substance Composition:

active substance 20 mg lactose 120 mg corn starch 40 mg magnesiumstearate 2 mg Povidone K 25 18 mg

Preparation:

Active substance, lactose and corn starch are homogeneously mixed;granulated with an aqueous solution of Povidone; mixed with magnesiumstearate; compressed in a tablet press; weight of tablet 200 mg.

Example X Capsules Containing 20 mg Active Substance Composition:

active substance 20 mg corn starch 80 mg highly dispersed silica 5 mgmagnesium stearate 2.5 mg

Preparation:

Active substance, corn starch and silica are homogeneously mixed; mixedwith magnesium stearate; the mixture is packed into size for 3 hardgelatine capsules in a capsule filling machine.

Example XI Suppositories Containing 50 mg of Active SubstanceComposition:

active substance  50 mg hard fat (adeps solidus) q.s. ad 1700 mg

Preparation:

Hard fat is melted at about 38° C.; ground active substance ishomogeneously dispersed in the molten hard fat; after cooling to about35° C. it is poured into chilled moulds.

Example XII Injectable Solution Containing 10 mg of Active Substance Per1 ml Composition:

active substance 10 mg mannitol 50 mg human serum albumin 10 mg waterfor injections ad 1 ml

Preparation:

Mannitol is dissolved in water for injections (WfI); human serum albuminis added; active ingredient is dissolved with heating; made up tospecified volume with WfI; transferred into ampoules under nitrogen gas.

1. Compounds of general formulae Ia and Ib

wherein R¹ denotes a group of general formula II

wherein G-L denotes N, N—C(R^(1.1))₂, C═C(R^(1.1)), C═N, C(R^(1.1)),C(R^(1.1))—C(R^(1.1))₂, C(R^(1.1))—C(R^(1.1))₂—C(R^(1.1))₂,C═C(R^(1.1))—C(R^(1.1))₂, C(R^(1.1))—C(R^(1.1))═C(R^(1.1)),C(R^(1.1))—C(R^(1.1))₂—N(R^(1.2)), C═C(R^(1.1))—N(R^(1.2)),C(R^(1.1))—C(R^(1.1))═N, C(R^(1.1))—N(R^(1.2))—C(R^(1.1))₂,C═N—C(R^(1.1))₂, C(R^(1.1))—N═C(R^(1.1)),C(R^(1.1))—N(R^(1.2))—N(R^(1.2)), C═N—N(R^(1.2)),N—C(R^(1.1))₂—C(R^(1.1))₂, N—C(R^(1.1))═C(R^(1.1)),N—C(R^(1.1))₂—N(R^(1.2)), N—C(R^(1.1))═N, N—N(R^(1.2))—C(R^(1.1))₂ orN—N═C(R^(1.1)), Q-T denotes C(R^(1.3))₂—C(R^(1.3))₂,C(R^(1.3))═C(R^(1.3)), N═C(R^(1.3)), C(R^(1.3))₂—C(═O),C(═O)—C(R^(1.3))₂, C(R^(1.3))₂—S(O), or C(R^(1.3))₂—N(R^(1.3)), while agroup C(R^(1.3))₂ contained in Q-T may also denote a cyclic group whichis selected from among C₃₋₆-cycloalkyl, C₅₋₆-cycloalkenyl orheterocyclyl, or in a group C(R^(1.3))₂—C(R^(1.3))₂,C(R^(1.3))═C(R^(1.3)) or C(R^(1.3))₂—N(R^(1.3)) contained in Q-T in eachcase a group R^(1.3) together with an adjacent group R^(1.3) and theatoms to which these groups are bound may also denote a C₃₋₆-cycloalkyl,C₅₋₆-cycloalkenyl, heterocyclyl, aryl or heteroaryl group, which may besubstituted independently of one another by 1, 2 or 3 substituentsR^(1.3.1), R^(1.1) denotes (a) H, (b) C₁₋₆-alkyl, —CN, —OH,—O—C₁₋₃-alkyl, (c) a C₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein eachmethylene group is substituted by up to two fluorine atoms and eachmethyl group is substituted by up to three fluorine atoms, R^(1.2)denotes H or C₁₋₆-alkyl, R^(1.3) independently of one another denote (a)H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₆-cycloalkyl, (b) an arylgroup optionally substituted by 1, 2 or 3 substituents R^(1.3.2),wherein the substituents R^(1.3.2) may be identical or different, (c) aheteroaryl group optionally substituted by 1, 2 or 3 substituentsR^(1.3.2), wherein the substituents R^(1.3.2) may be identical ordifferent, (d) a heterocyclic group optionally substituted by 1, 2 or 3substituents R^(1.3.2), wherein the substituents R^(1.3.2) may beidentical or different, R^(1.3.1) denotes (a) H, halogen, C₁₋₆-alkyl,C₃₋₆-cycloalkyl, (b) —O—R^(1.3.1.1),—O—C₁₋₆-alkylene-NR^(1.3.1.2)R^(1.3.1.3), —O—(CH₂)_(s)—O—R^(1.3.1.1),—CO₂—R^(1.3.1.1), —C(O)—NR^(1.3.1.2)R^(1.3.1.3),—O—C(O)—NR^(1.3.1.2)R^(1.3.1.3),—NR^(1.3.1.1)—C(O)—NR^(1.3.1.2)R^(1.3.1.3),—NR^(1.3.1,2)—C(O)—R^(1.3.1.3), —NR^(1.3.1,2)—C(O)—O—R^(1.3.1.3),—SO₂—NR^(1.3.1.2)R^(1.3.1.3), —NR^(1.3.1,2)—SO₂—R^(1.3.1.3),—S(O)_(m)—R^(1.3.1.2), —CN, —NR^(1.3.1.2)R^(1.3.1.3),—NR^(1.3.1.1)—C(O)—NR^(1.3.1.2)R^(1.3.1.3), —O—C(O)—R^(1.3.1.1), (c) aC₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, (d) an aryl group substitutedby 1, 2 or 3 substituents R^(1.3.1.1), wherein the substituentsR^(1.3.1.1) may be identical or different, (e) a heteroaryl groupsubstituted by 1, 2 or 3 substituents R^(1.3.1.1), wherein thesubstituents R^(1.3.1.1) may be identical or different, (f) aheterocyclic group substituted by 1, 2 or 3 substituents R^(1.3.1.1),wherein the substituents R^(1.3.1.1) may be identical or different,R^(1.3.2) denotes (a) halogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, (b)—O—R^(1.3.2.1), —O—(CH₂)_(s)—O—R^(1.3.2.1), —CO₂R^(1.3.2.1),—C(O)—NR^(1.3.2.2)R^(1.3.2.3), —O—(CO)—NR^(1.3.2.2)R^(1.3.2.3),—N(R^(1.3.2.1))—C(O)—NR^(1.3.2.2)R^(1.3.2.3),—N(R^(1.3.2.2))—C(O)—R^(1.3.2.3), —N(R^(1.3.2.2))—C(O)—O—R^(1.3.2.3),—SO₂—NR^(1.3.2.2)R^(1.3.2.3), —N(R^(1.3.2.2))—SO₂—R^(1.3.2.3),—S(O)_(m)—R^(1.3.2.2), —CN, —NR^(1.3.2.2)R^(1.3.2.3),—N(R^(1.3.2.1))—C(O)—NR^(1.3.2.2)R^(1.3.2.3), —O—C(O)—R^(1.3.2.1) or (c)a C₁₋₃-alkyl group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, R^(1.3.1.1) denotes (a) H, (b) C₁₋₆-alkyl,C₃₋₆-cycloalkyl, aryl, heteroaryl, benzyl which may be substituted by agroup R^(1.3.1.1.1), or (c) a C₁₋₃-alkyl group wherein each methylenegroup is substituted by up to two fluorine atoms and each methyl groupis substituted by up to three fluorine atoms, R^(1.3.1.1.1) denoteshalogen, HO— or C₁₋₆-alkyl-O—, R^(1.3.1.2) denotes (a) H, (b)C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl or benzyl, wherein thegroups may be unsubstituted or substituted by halogen, HO— orC₁₋₆-alkyl-O—, or (c) a C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R^(1.3.1.3) denotes (a) H,C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl or benzyl, wherein thegroups may be unsubstituted or substituted by halogen, HO— orC₁₋₆-alkyl-O—, or (c) a C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, or R^(1.3.1.2) andR^(1.3.1.3) together may also form a ring which is selected from amongazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl,wherein the ring may be unsubstituted or substituted by 1, 2 or 3substituents R^(1.3.1.1) or fluorine, wherein the substituentsR^(1.3.1.1) are independent of one another, R^(1.3.2.1) denotes (a) H,(b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, benzyl which may besubstituted by a group R^(1.3.2.1.1), or (c) a C₁₋₃-alkyl group whereineach methylene group is substituted by up to two fluorine atoms and eachmethyl group is substituted by up to three fluorine atoms, R^(1.3.2.1.1)denotes halogen, HO— or C₁₋₆-alkyl-O—, R^(1.3.2.2) denotes (a) H, (b)C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl or benzyl, wherein thegroups may be unsubstituted or substituted by halogen, HO— orC₁₋₆-alkyl-O—, or (c) a C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R^(1.3.2.3) denotes (a) H,(b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl or benzyl, wherein thegroups may be unsubstituted or substituted by halogen, HO— orC₁₋₆-alkyl-O—, or (c) a C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, or R^(1.3.2.2) andR^(1.3.2.3) together may also form a ring which is selected from amongazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl,wherein the ring may be unsubstituted or substituted by 1, 2 or 3substituents R^(1.3.2.1) or fluorine, wherein the substituentsR^(1.3.2.1) are independent of one another, m denotes one of the numbers0, 1 or 2, s denotes one of the numbers 1, 2 or 3, R² denotes (a) H, (b)F, —CN, C₁₋₃-alkyl, —CO₂—R^(2.1) or (c) a C₁₋₃-alkyl group wherein eachmethylene group is substituted by up to two fluorine atoms and eachmethyl group is substituted by up to three fluorine atoms, R^(2.1)denotes H or C₁₋₆-alkyl, R³ denotes (a) H, (b) C₁₋₆-alkylene-R^(3.1),(c) a C₃₋₆-cycloalkyl group substituted by one or two groups R^(3.2),(d) a C₅₋₇-cycloalkenyl group substituted by one or two groups R^(3.2),(e) an aryl group substituted by one or two groups R^(3.2), (f) aheterocyclyl group substituted by one or two groups R^(3.2), (g) aC₅₋₇-cycloalkyl group which may be fused to an aryl or heteroaryl groupand is additionally substituted by one or two groups R^(3.2), (h) aheteroaryl group substituted by one or two groups R^(3.2), (i) aC₁₋₃-alkyl group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, R^(3.1) denotes (a) H, (b) an aryl group substituted bythe groups R^(3.1.1) and R^(3.1.2), (c) a heteroaryl group substitutedby the groups R^(3.1.1) and R^(3.1.2), R^(3.1.1) denotes (a) H, (b)halogen, C₁₋₃-alkyl, —OH, —CN, —O—C₁₋₃-alkyl, —O—C(O)—C₁₋₃-alkyl,—NR^(3.1.1.1)R^(3.1.1.2), —S(O)_(m)—C₁₋₃-alkyl,—NR^(3.1.1.1)—C(O)—C₁₋₃-alkyl, —C(O)—NR^(3.1.1.1)R^(3.1.12),—C(O)—O—R^(3.1.1.3), —NR^(3.1.1.1)—C(O)—O—C₁₋₃-alkyl,—O—C(O)—NR^(3.1.1.1)R^(3.1.1.2), (c) a C₁₋₃-alkyl or —O—C₁₋₃-alkyl groupwherein each methylene group is substituted by up to two fluorine atomsand each methyl group is substituted by up to three fluorine atoms,R^(3.1.1.1) denotes H, C₁₋₃-alkyl and R^(3.1.1.2) denotes H, C₁₋₃-alkyl,or R^(3.1.1.1) and R^(3.1.1.2) together with the nitrogen atom to whichthey are bound also denote a group which is selected from morpholinyl,thiomorpholinyl, piperidinyl, piperidonyl, piperazinyl, pyrrolidinyl andazetidinyl, while the group may additionally be substituted by one ortwo substituents selected from F, —OH, —O—C₁₋₃-alkyl, —OCF₃, C₁₋₃-alkyland CF₃, R^(3.1.1.3) denotes H, C₁₋₃-alkyl, R^(3.1.2) denotes (a) H, (b)halogen, C₁₋₃-alkyl, —OH, —CN, —O—C₁₋₃-alkyl, (c) a C₁₋₃-alkyl or—O—C₁₋₃-alkyl group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, or R^(3.2) independently of one another denote (a) H,(b) halogen, C₁₋₃-alkyl, —OH, —CN, —O—C₁₋₃-alkyl, —O—C(O)—C₁₋₃-alkyl,—NR^(3.2.1)R^(3.2.2), —S(O)_(m)—C₁₋₃-alkyl, —NR^(3.2.1)—C(O)—C₁₋₃-alkyl,—C(O)—NR^(3.2.1)R^(3.2.2), —C(O)—O—R^(3.2.3),—NR^(3.2.1)—C(O)—O—C₁₋₃-alkyl, —O—C(O)—NR^(3.2.1)R^(3.2.2), (c) aC₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R^(3.2.1) denotes H,C₁₋₃-alkyl and R^(3.2.2) denotes H, C₁₋₃-alkyl, or R^(3.2.1) andR^(3.2.2) together with the nitrogen atom to which they are bound alsodenote a group which is selected from morpholinyl, thiomorpholinyl,piperidinyl, piperidonyl, piperazinyl, pyrrolidinyl and azetidinyl,while the group may additionally be substituted by one or twosubstituents selected from F, —OH, —O—C₁₋₃-alkyl, —OCF₃, C₁₋₃-alkyl andCF₃, R^(3.2.3) denotes H, C₁₋₃-alkyl, R⁴ denotes (a) H, (b)C₁₋₆-alkylene-R^(4.1), (c) a C₃₋₆-cycloalkyl group substituted by one ortwo groups R^(4.2), (d) a C₅₋₇-cycloalkenyl group substituted by one ortwo groups R^(4.2), (e) an aryl group substituted by one or two groupsR^(4.2), (f) a heterocyclyl group substituted by one or two groupsR^(4.2), (g) a C₅₋₇-cycloalkyl group which may be fused to an aryl orheteroaryl group, while the resultant bicyclic group is additionallysubstituted by one or two groups R^(4.2), (h) a heteroaryl groupsubstituted by one or two groups R^(4.2), (i) a C₁₋₃-alkyl group whereineach methylene group is substituted by up to two fluorine atoms and eachmethyl group is substituted by up to three fluorine atoms, R^(4.1)denotes (a) H, (b) an aryl group substituted by the groups R^(4.1.1) andR^(4.1.2), (c) a heteroaryl group substituted by the groups R^(4.1.1)and R^(4.1.2), R^(4.1.1) denotes (a) H, (b) halogen, C₁₋₃-alkyl, —OH,—CN, —O—C₁₋₃-alkyl, —O—C(O)—C₁₋₃-alkyl, —NR^(4.1.1.1)R^(4.1.1.2),—S(O)_(m)—C₁₋₃-alkyl, —NR^(4.1.1.1)—C(O)—C₁₋₃-alkyl,—C(O)—NR^(4.1.1.1)R^(4.1.1.2), —C(O)—O—R^(4.1.1.3),—O—C(O)—NR^(4.1.1.1)R^(4.1.1.2), (c) a C₁₋₃-alkyl or —O—C₁₋₃-alkyl groupwherein each methylene group is substituted by up to two fluorine atomsand each methyl group is substituted by up to three fluorine atoms,R^(4.1.1.1) denotes H, C₁₋₃-alkyl and R^(4.1.1.2) denotes H, C₁₋₃-alkyl,or R^(4.1.1.1) and R^(4.1.1.2) together with the nitrogen atom to whichthey are bound also denote a group which is selected from morpholinyl,thiomorpholinyl, piperidinyl, piperidonyl, piperazinyl, pyrrolidinyl andazetidinyl, while the group may additionally be substituted by one ortwo substituents selected from F, —OH, —O—C₁₋₃-alkyl, —OCF₃, C₁₋₃-alkyland CF₃, R^(4.1.1.3) denotes H, C₁₋₃-alkyl, R^(4.1.2) denotes (a) H, (b)halogen, C₁₋₃-alkyl, —OH, —CN, —O—C₁₋₃-alkyl, (c) a C₁₋₃-alkyl or—O—C₁₋₃-alkyl group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, or R^(4.2) independently of one another denote (a) H,(b) halogen, C₁₋₃-alkyl, —OH, —CN, —O—C₁₋₃-alkyl, —O—C(O)—C₁₋₃-alkyl,—NR^(4.2.1)R^(4.2.2), —S(O)_(m)—C₁₋₃-alkyl, —NR^(4.2.1)—C(O)—C₁₋₃-alkyl,—C(O)—NR^(4.2.1)R^(4.2.2), —C(O)—O—R^(4.2.3),—NR^(4.2.1)—C(O)—O—C₁₋₃-alkyl, —O—C(O)—NR^(4.2.1)R^(4.2.2), (c) aC₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R^(4.2.1) denotes H,C₁₋₃-alkyl and R^(4.2.2) denotes H, C₁₋₃-alkyl, or R^(4.2.1) andR^(4.2.2) together with the nitrogen atom to which they are bound alsodenote a group which is selected from morpholinyl, thiomorpholinyl,piperidinyl, piperidonyl, piperazinyl, pyrrolidinyl and azetidinyl,while the group may additionally be substituted by one or twosubstituents selected from F, —OH, —O—C₁₋₃-alkyl, —OCF₃, C₁₋₃-alkyl andCF₃, R^(4.2.3) denotes H, C₁₋₃-alkyl, R³ and R⁴ together with thenitrogen atom to which they are bound denote: (a) a saturated 5-, 6- or7-membered heterocyclic group which is substituted at a carbon atom by agroup R^(4.3) or by two groups R^(4.3) and R^(4.4), (b) a saturated 5-,6- or 7-membered heterocyclic group which is substituted at two adjacentcarbon atoms by in each case a group R^(4.3) and R^(4.4), (c) asaturated 5-, 6- or 7-membered heterocyclic group which is substitutedat a carbon atom by a group R^(4.3) or by two groups R^(4.3) and R^(4.4)and is additionally fused to a 5-, 6- or 7-membered cycloalkyl orheterocyclyl group, while the fused-on cycloalkyl or heterocyclyl groupis substituted by 1, 2 or 3 groups R^(4.5), (d) a monounsaturated 5-, 6-or 7-membered heterocyclic group which is substituted at a carbon atomby a group R^(4.3) or by two groups R^(4.3) and R^(4.4) and isadditionally fused to a phenyl group, while the fused-on phenyl group issubstituted by 1, 2 or 3 groups R^(4.5), (e) a monounsaturated 5-, 6- or7-membered heterocyclic group which is substituted at a carbon atom by agroup R^(4.3) or by two groups R^(4.3) and R^(4.4) and is additionallyfused to a 5- or 6-membered heteroaryl group, while the fused-onheteroaryl group is substituted by 1, 2 or 3 groups R^(4.5), or (f) aheteroaryl group which is substituted at 1, 2 or 3 carbon atoms by ineach case a group R^(4.5), R^(4.3) independently of one another denote(a) H, C₁₋₃-alkyl, C₂₋₆-alkynyl, aryl, —C₁₋₃-alkylene-R^(4.3.1),C₁₋₃-alkyl-O—C(O)—, HO—C(O)—, F, —O—C₁₋₃-alkyl, —OH, —CN, (b) aC₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R^(4.3.1) denotes H,C₁₋₃-alkyl-O—C(O)—, —NH₂, (C₁₋₄-alkyl)-NH—, (C₁₋₄-alkyl)₂N,C₃₋₆-cycloalkyl-, heterocyclyl, heteroaryl, aryl, R^(4.4) denotes (a) H,C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl or (b) a C₁₋₃-alkyl or —O—C₁₋₃-alkylgroup wherein each methylene group is substituted by up to two fluorineatoms and each methyl group is substituted by up to three fluorineatoms, R^(4.3) and R^(4.4) together with the carbon atoms to which theyare bound also denote a C₃₋₆-cycloalkyl, C₅₋₆-cycloalkenyl orheterocyclyl group, R^(4.5) independently of one another denote (a) H,(b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, —S(O), —C₁₋₃-alkyl,—NR^(4.5.2)R^(4.5.3), —CN, —C(O)—O—R^(4.5.1), —C(O)—NR^(4.5.2)R^(4.5.3),(c) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, (d) aryl, heteroaryl,R^(4.5.1) denotes H, C₁₋₃-alkyl, R^(4.5.2) denotes H, C₁₋₃-alkyl,R^(4.5.3) denotes H, C₁₋₃-alkyl, or R^(4.5.2) and R^(4.5.3) togetherwith the nitrogen atom to which they are bound also denote a group whichis selected from morpholinyl, thiomorpholinyl, piperidinyl, piperidonyl,piperazinyl, pyrrolidinyl and azetidinyl, while the group mayadditionally be substituted by one or two substituents selected from F,—OH, —OCF₃, C₁₋₃-alkyl and CF₃, R⁵ denotes H, —CH₂—R^(5.1) or benzyl,and R^(5.1) denotes a C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, the tautomers, thediastereomers, the enantiomers, the hydrates, the mixtures thereof andthe salts thereof as well as the hydrates of the salts, particularly thephysiologically acceptable salts thereof with inorganic or organic acidsor bases.
 2. Compounds of general formulae Ia and Ib according to claim1, wherein R², R³, R⁴ and R⁵ are defined as in claim 1 and R¹ denotes agroup of general formula II

wherein G-L denotes N, N—C(R^(1.1))₂, C═C(R^(1.1)), C═N, C(R^(1.1)),C(R^(1.1))—C(R^(1.1))₂, C(R^(1.1))—C(R^(1.1))₂—C(R^(1.1))₂,C═C(R^(1.1))—C(R^(1.1))₂, C(R^(1.1))—C(R^(1.1))═C(R^(1.1)),C(R^(1.1))—C(R^(1.1))₂—N(R^(1.2)), C═C(R^(1.1))—N(R^(1.2)),C(R^(1.1))—C(R^(1.1))═N, C(R^(1.1))—N(R^(1.2))—C(R^(1.1))₂,C═N—C(R^(1.1))₂, C(R^(1.1))—N═C(R^(1.1)),C(R^(1.1))—N(R^(1.2))—N(R^(1.2)), C═N—N(R^(1.2)),N—C(R^(1.1))₂—C(R^(1.1))₂, N—C(R^(1.1))═C(R^(1.1)),N—C(R^(1.1))₂—N(R^(1.2)), N—C(R^(1.1))═N, N—N(R^(1.2))—C(R^(1.1))₂ orN—N═C(R^(1.1)), Q-T denotes C(R^(1.3))₂—C(R^(1.3))₂,C(R^(1.3))═C(R^(1.3)), N═C(R^(1.3)), C(R^(1.3))₂—C(═O),C(═O)—C(R^(1.3))₂, C(R^(1.3))₂—S(O)_(m) or C(R^(1.3))₂—N(R^(1.3)), whilea group C(R^(1.3))₂ contained in Q-T may also denote a cyclic groupwhich is selected from among cyclobutyl, cyclopentyl, cyclohexyl,cyclopentenyl, cyclohexenyl, dioxanyl, morpholinyl, thiomorpholinyl,thiomorpholinyl-5-oxide, thiomorpholinyl-5-dioxide, azetidinyl,pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl andpiperazinyl, or in a group C(R^(1.3))₂—C(R^(1.3))₂,C(R^(1.3))═C(R^(1.3)) or C(R^(1.3))₂—N(R^(1.3)) contained in Q-T in eachcase a group R^(1.3) together with an adjacent group R^(1.3) and theatoms to which these groups are bound may also denote a group selectedfrom cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl,dioxanyl, phenyl, naphthyl, thienyl, thiazolyl, thiazolinyl, oxazolyl,oxazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolinyl, quinolinyl,isoquinolinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl-S-oxide,thiomorpholinyl-S-dioxide, 1H-quinolinyl-2-one, azetidinyl,pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydropyridyl, furanyl, dihydrofuranyl, dihydropyranyl andpiperazinyl, which may be substituted independently of one anotherdenote by 1, 2 or 3 substituents R^(1.3.1), R^(1.1) denotes (a) H, (b)C₁₋₆-alkyl, —CN, —OH, —O—C₁₋₃-alkyl, (c) a C₁₋₃-alkyl- or C₁₋₃-alkyl-O—group wherein each methylene group is substituted by up to two fluorineatoms and each methyl group is substituted by up to three fluorineatoms, R^(1.2) denotes H or C₁₋₆-alkyl, R^(1.3) independently of oneanother denote (a) H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₃₋₆-cycloalkyl, (b) an aryl group optionally substituted by 1, 2 or 3substituents R^(1.3.2), wherein the substituents R^(1.3.2) may beidentical or different, (c) a heteroaryl group optionally substituted by1, 2 or 3 substituents R^(1.3.2), wherein the substituents R^(1.3.2) maybe identical or different, (d) a heterocyclic group optionallysubstituted by 1, 2 or 3 substituents R^(1.3.2), wherein thesubstituents R^(1.3.2) may be identical or different, R^(1.3.1) denotes(a) H, halogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, (b) —O—R^(1.3.1.1),—O—C₁₋₆-alkylene-NR^(1.3.1.2)R^(1.3.1.3), —I—(CH₂)_(s)—O—R^(1.3.1.1),—CO₂—R^(1.3.1.1), C(O)—NR^(1.3.1.2)R^(1.3.1.3),—O—C(O)—NR^(1.3.1.2)R^(1.3.1.3),—NR^(1.3.1.1)—C(O)—NR^(1.3.1.2)R^(1.3.1.3),—NR^(1.3.1,2)—C(O)—R^(1.3.1.3), —NR^(1.3.1,2)—C(O)—O—R^(1.3.1.3),—SO₂—NR^(1.3.1.2)R^(1.3.1.3), —NR^(1.3.1,2)—SO₂—R^(1.3.1.3),—S(O)_(m)—R^(1.3.1.2), —CN, —NR^(1.3.1.2)R^(1.3.1.3),—NR^(1.3.1.1)—C(O)—NR^(1.3.1.2)R^(1.3.1.3), —O—C(O)—R^(1.3.1.1), (c) aC₁₋₃-alkyl or C₁₋₃-alkyl-O— group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, (d) an aryl group substitutedby 1, 2 or 3 substituents R^(1.3.1.1), wherein the substituentsR^(1.3.1.1) may be identical or different, (e) a heteroaryl groupsubstituted by 1, 2 or 3 substituents R^(1.3.1.1), wherein thesubstituents R^(1.3.1.1) may be identical or different, (f) aheterocyclic group substituted by 1, 2 or 3 substituents R^(1.3.1.1),wherein the substituents R^(1.3.1.1) may be identical or different,R^(1.3.2) denotes (a) halogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, (b)—O—R^(1.3.2.1), —O—(CH₂)_(s)—O—R^(1.3.2.1), —CO₂R^(1.3.2.1),—C(O)—NR^(1.3.2.2)R^(1.3.2.3), —O—(CO)—NR^(1.3.2.2)R^(1.3.2.3),—N(R^(1.3.2.1))—C(O)—NR^(1.3.2.2)R^(1.3.2.3),—N(R^(1.3.2.2))—C(O)—R^(1.3.2.3), —N(R^(1.3.2.2))—C(O)—O—R^(1.3.2.3),—SO₂—NR^(1.3.2.2)R^(1.3.2.3), —N(R^(1.3.2.2))—SO₂—R^(1.3.2.3),—S(O)_(m)—R^(1.3.2.2), —CN, —NR^(1.3.2.2)R^(1.3.2.3),—N(R^(1.3.2.1))—C(O)—NR^(1.3.2.2)R^(1.3.2.3), —O—C(O)—R^(1.3.2.1) or (c)a C₁₋₃-alkyl group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, R^(1.3.1.1) denotes (a) H, (b) C₁₋₆-alkyl,C₃₋₆-cycloalkyl, aryl, heteroaryl, benzyl which may be substituted by agroup R^(1.3.1.1.1), or (c) a C₁₋₃-alkyl group wherein each methylenegroup is substituted by up to two fluorine atoms and each methyl groupis substituted by up to three fluorine atoms, R^(1.3.1.1.1) denoteshalogen, HO— or C₁₋₆-alkyl-O—, R^(1.3.1.2) denotes (a) H, (b)C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl or benzyl, wherein thegroups may be unsubstituted or substituted by halogen, HO— orC₁₋₆-alkyl-O—, or (c) a C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R^(1.3.1.3) denotes (a) H,(b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl or benzyl, wherein thegroups may be unsubstituted or substituted by halogen, HO— orC₁₋₆-alkyl-O—, or (c) a C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, or R^(1.3.1.2) andR^(1.3.1.3) together may also form a ring which is selected from amongazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl,wherein the ring may be unsubstituted or substituted by 1, 2 or 3substituents R^(1.3.1.1) or fluorine, wherein the substituentsR^(1.3.1.1) are independent of one another, R^(1.3.2.1) denotes (a) H,(b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, benzyl which may besubstituted by a group R^(1.3.2.1.1), or (c) a C₁₋₃-alkyl group whereineach methylene group is substituted by up to two fluorine atoms and eachmethyl group is substituted by up to three fluorine atoms, R^(1.3.2.1.1)denotes halogen, HO— or C₁₋₆-alkyl-O—, R^(1.3.2.2) denotes (a) H, (b)C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl or benzyl, wherein thegroups may be unsubstituted or substituted by halogen, HO— orC₁₋₆-alkyl-O—, or (c) a C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R^(1.3.2.3) denotes (a) H,(b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl or benzyl, wherein thegroups may be unsubstituted or substituted by halogen, HO— orC₁₋₆-alkyl-O—, or (c) a C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, or R^(1.3.2.2) andR^(1.3.2.3) together may also form a ring which is selected from amongazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl,wherein the ring may be unsubstituted or substituted by 1, 2 or 3substituents R^(1.3.2.1) or fluorine, wherein the substituentsR^(1.3.2.1) are independent of one another, m denotes one of the numbers0, 1 or 2 and s denotes one of the numbers 1, 2 or 3, the tautomers, thediastereomers, the enantiomers, the hydrates, the mixtures thereof andthe salts thereof as well as the hydrates of the salts, particularly thephysiologically acceptable salts thereof with inorganic or organic acidsor bases.
 3. Compounds of general formulae Ia and Ib according to claim1, wherein R², R³, R⁴ and R⁵ are defined as in claim 1 and R¹ denotes agroup of general formulae

wherein Q-T denotes C(R^(1.3))₂—C(R^(1.3))₂, C(R^(1.3))═C(R^(1.3)),N═C(R^(1.3)), C(R^(1.3))₂—C(═O), C(═O)—C(R^(1.3))₂, C(R^(1.3))₂—S(O), orC(R^(1.3))₂—N(R^(1.3)), while in a group C(R^(1.3))₂—C(R^(1.3))₂,C(R^(1.3))═C(R^(1.3)) or C(R^(1.3))₂—N(R^(1.3)) contained in Q-T in eachcase a group R^(1.3) together with an adjacent group R^(1.3) and theatoms to which these groups are bound may also denote a group selectedfrom cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl,dioxanyl, phenyl, naphthyl, thienyl, thiazolyl, thiazolinyl, oxazolyl,oxazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolinyl, quinolinyl,isoquinolinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl-S-oxide,thiomorpholinyl-S-dioxide, azetidinyl, pyrrolidinyl, piperidinyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridyl, furanyl,dihydrofuranyl, dihydropyranyl and piperazinyl, which may be substitutedindependently of one another denote by 1, 2 or 3 substituents R^(1.3.1),R^(1.1) denotes (a) H, (b) C₁₋₆-alkyl, —CN, —OH, —O—C₁₋₃-alkyl, (c) aC₁₋₃-alkyl- or C₁₋₃-alkyl-O— group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R^(1.3) independently of oneanother denote (a) H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₃₋₆-cycloalkyl, (b) an aryl group optionally substituted by 1, 2 or 3substituents R^(1.3.2), wherein the substituents R^(1.3.2) may beidentical or different, (c) a heteroaryl group optionally substituted by1, 2 or 3 substituents R^(1.3.2), wherein the substituents R^(1.3.2) maybe identical or different, (d) a heterocyclic group optionallysubstituted by 1, 2 or 3 substituents R^(1.3.2), wherein thesubstituents R^(1.3.2) may be identical or different, R^(1.3.1) denotes(a) H, halogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, (b) —O—R^(1.3.1.1),—O—C₁₋₆-alkylene-NR^(1.3.1.2)R^(1.3.1.3), —CO₂R^(1.3.1.1),—C(O)NR^(1.3.1.2)R^(1.3.1.3), —SO₂—NR^(1.3.1.2)R^(1.3.1.3),—N(R^(1.3.1.2))—SO₂—R^(1.3.1.3), —S(O)_(m)—R^(1.3.1.2), —CN,—NR^(1.3.1.2)R^(1.3.1.3), —O—C(O)—R^(1.3.1.1) or (c) a C₁₋₃-alkyl groupwherein each methylene group is substituted by up to two fluorine atomsand each methyl group is substituted by up to three fluorine atoms,R^(1.3.2) denotes (a) halogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, (b)—O—R^(1.3.2.1), —O—(CH₂)_(s)—O—R^(1.3.2.1), —CO₂R^(1.3.2.1),—S(O)_(m)—R^(1.3.2.2), —CN, —O—C(O)—R^(1.3.2.1) or (c) a C₁₋₃-alkylgroup wherein each methylene group is substituted by up to two fluorineatoms and each methyl group is substituted by up to three fluorineatoms, R^(1.3.1.1) denotes (a) H, (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl,heteroaryl, benzyl which may be substituted by a group R^(1.3.1.1.1), or(c) a C₁₋₃-alkyl group wherein each methylene group is substituted by upto two fluorine atoms and each methyl group is substituted by up tothree fluorine atoms, R^(1.3.1.1.1) denotes halogen, HO— orC₁₋₆-alkyl-O—, R^(1.3.1.2) denotes (a) H, (b) C₁₋₆-alkyl,C₃₋₆-cycloalkyl, aryl, heteroaryl, or benzyl, wherein the groups may beunsubstituted or substituted by halogen, HO— or C₁₋₆-alkyl-O—, or (c) aC₁₋₃-alkyl group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, R^(1.3.1.3) denotes (a) H, (b) C₁₋₆-alkyl,C₃₋₆-cycloalkyl, aryl, heteroaryl, or benzyl, wherein the groups may beunsubstituted or substituted by halogen, HO— or C₁₋₆-alkyl-O—, or (c) aC₁₋₃-alkyl group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, or R^(1.3.1.2) and R^(1.3.1.3) together may also form aring which is selected from among azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl and morpholinyl, wherein the ring may be unsubstituted orsubstituted by 1, 2 or 3 substituents R^(1.3.1.1), wherein thesubstituents R^(1.3.1.1) are independent of one another, R^(1.3.2.1)denotes (a) H, (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, benzylwhich may be substituted by a group R^(1.3.2.1.1), or (c) a C₁₋₃-alkylgroup wherein each methylene group is substituted by up to two fluorineatoms and each methyl group is substituted by up to three fluorineatoms, R^(1.3.2.1.1) denotes halogen, HO— or C₁₋₆-alkyl-O—, R^(1.3.2.2)denotes (a) H, (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, orbenzyl, wherein the groups may be unsubstituted or substituted byhalogen, HO— or C₁₋₆-alkyl-O—, or (c) a C₁₋₃-alkyl group wherein eachmethylene group is substituted by up to two fluorine atoms and eachmethyl group is substituted by up to three fluorine atoms, R^(1.3.2.3)denotes (a) H, (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, orbenzyl, wherein the groups may be unsubstituted or substituted byhalogen, HO— or C₁₋₆-alkyl-O—, or (c) a C₁₋₃-alkyl group wherein eachmethylene group is substituted by up to two fluorine atoms and eachmethyl group is substituted by up to three fluorine atoms, orR^(1.3.2.2) and R^(1.3.2.3) together may also form a ring which isselected from among azetidinyl, pyrrolidinyl, piperidinyl, piperazinyland morpholinyl, wherein the ring may be unsubstituted or substituted by1, 2 or 3 substituents R^(1.3.2.1), wherein the substituents R^(1.3.2.1)are independent of one another, m denotes one of the numbers 0, 1 or 2and s denotes one of the numbers 1, 2 or 3, the tautomers, thediastereomers, the enantiomers, the hydrates, the mixtures thereof andthe salts thereof as well as the hydrates of the salts, particularly thephysiologically acceptable salts thereof with inorganic or organic acidsor bases.
 4. Compounds of general formulae Ia and Ib according to claim1, wherein R², R³, R⁴ and R⁵ are defined as in claim 1 and R¹ denotes agroup of general formulae

wherein Q-T denotes C(R^(1.3))₂—C(R^(1.3))₂, C(R^(1.3))═C(R^(1.3)),N═C(R^(1.3)), C(R^(1.3))₂—C(═O), C(═O)—C(R^(1.3))₂, C(R^(1.3))₂—S(O), orC(R^(1.3))₂—N(R^(1.3)), while in a group C(R^(1.3))₂—C(R^(1.3))₂,C(R^(1.3))═C(R^(1.3)) or C(R^(1.3))₂—N(R^(1.3)) contained in Q-T in eachcase a group R^(1.3) together with an adjacent group R^(1.3) and theatoms to which these groups are bound may also denote a group selectedfrom cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, dioxanyl,phenyl, naphthyl, thienyl, pyridyl, pyrazinyl, pyridazinyl, quinolinyl,isoquinolinyl, morpholinyl, pyrrolidinyl, piperidinyl,tetrahydrofuranyl, tetrahydropyranyl and piperazinyl, which may besubstituted independently of one another denote by 1, 2 or 3substituents R^(1.3.1), R^(1.1) denotes (a) H, (b) C₁₋₆-alkyl, —CN, —OH,—O—C₁₋₃-alkyl, (c) a C₁₋₃-alkyl- or C₁₋₃-alkyl-O— group wherein eachmethylene group is substituted by up to two fluorine atoms and eachmethyl group is substituted by up to three fluorine atoms, R^(1.3)denotes (a) H, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, (b) an aryl group optionallysubstituted by 1, 2 or 3 substituents R^(1.3.2), wherein thesubstituents R^(1.3.2) may be identical or different, (c) a heteroarylgroup optionally substituted by 1, 2 or 3 substituents R^(1.3.2),wherein the substituents R^(1.3.2) may be identical or different, (d) aheterocyclic group optionally substituted by 1, 2 or 3 substituentsR^(1.3.2), wherein the substituents R^(1.3.2) may be identical ordifferent, R^(1.3.1) denotes (a) H, halogen, C₁₋₆-alkyl,C₃₋₆-cycloalkyl, (b) —O—R^(1.3.1.1),—O—C₁₋₆-alkylene-NR^(1.3.1.2)R^(1.3.1.3), —CO₂R^(1.3.1.1),—C(O)—NR^(1.3.1.2)R^(1.3.1.3), —SO₂—NR^(1.3.1.2)R^(1.3.1.3),—NR^(1.3.1,2)—SO₂—R^(1.3.1.3), —CN, —NR^(1.3.1.2)R^(1.3.1.3),—O—C(O)—R^(1.3.1.1) or (c) a C₁₋₃-alkyl group wherein each methylenegroup is substituted by up to two fluorine atoms and each methyl groupis substituted by up to three fluorine atoms, R^(1.3.2) denotes (a)halogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, (b) —O—R^(1.3.2.1),—O—(CH₂)_(s)—OR^(1.3.2.1), —CO₂R^(1.3.2.1), —S(O)_(m)—R^(1.3.2.2), —CN,—O—C(O)—R^(1.3.2.1) or (c) a C₁₋₃-alkyl group wherein each methylenegroup is substituted by up to two fluorine atoms and each methyl groupis substituted by up to three fluorine atoms, R^(1.3.1.1) denotes (a) H,(b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, benzyl which may besubstituted by a group R^(1.3.1.1.1), or (c) a C₁₋₃-alkyl group whereineach methylene group is substituted by up to two fluorine atoms and eachmethyl group is substituted by up to three fluorine atoms, R^(1.3.1.1.1)denotes halogen, HO— or C₁₋₆-alkyl-O—, R^(1.3.1.2) denotes (a) H, (b)C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, or benzyl, wherein thegroups may be unsubstituted or substituted by halogen, HO— orC₁₋₆-alkyl-O—, or (c) a C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R^(1.3.1.3) denotes (a) H,(b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, or benzyl, whereinthe groups may be unsubstituted or substituted by halogen, HO— orC₁₋₆-alkyl-O—, or (c) a C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, or R^(1.3.1.2) andR^(1.3.1.3) together may also form a ring which is selected from amongazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl,wherein the ring may be unsubstituted or substituted by 1, 2 or 3substituents R^(1.3.1.1), wherein the substituents R^(1.3.1.1) areindependent of one another, R^(1.3.2.1) denotes (a) H, (b) C₁₋₆-alkyl,C₃₋₆-cycloalkyl, aryl, heteroaryl, benzyl which may be substituted by agroup R^(1.3.2.1.1), or (c) a C₁₋₃-alkyl group wherein each methylenegroup is substituted by up to two fluorine atoms and each methyl groupis substituted by up to three fluorine atoms, R^(1.3.2.1.1) denoteshalogen, HO— or C₁₋₆-alkyl-O—, R^(1.3.2.2) denotes (a) H, (b)C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, or benzyl, wherein thegroups may be unsubstituted or substituted by halogen, HO— orC₁₋₆-alkyl-O—, or (c) a C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R^(1.3.2.3) denotes (a) H,(b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, or benzyl, whereinthe groups may be unsubstituted or substituted by halogen, HO— orC₁₋₆-alkyl-O—, or (c) a C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, or R^(1.3.2.2) andR^(1.3.2.3) together may also form a ring which is selected from amongazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl,wherein the ring may be unsubstituted or substituted by 1, 2 or 3substituents R^(1.3.2.1), wherein the substituents R^(1.3.2.1) areindependent of one another, m denotes one of the numbers 0, 1 or 2 and sdenotes one of the numbers 1, 2 or 3, the tautomers, the diastereomers,the enantiomers, the hydrates, the mixtures thereof and the saltsthereof as well as the hydrates of the salts, particularly thephysiologically acceptable salts thereof with inorganic or organic acidsor bases.
 5. Compounds of general formulae Ia and Ib according to claim1, wherein R², R³, R⁴ and R⁵ are defined as in claim 1 and R¹ denotes agroup of general formula

wherein R^(1.1) denotes (a) H, (b) C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, (c) aC₁₋₃-alkyl- or C₁₋₃-alkyl-O— group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R^(1.3) independently of oneanother denote (a) H, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, (b) a phenyl groupoptionally substituted by 1, 2 or 3 substituents R^(1.3.2), wherein thesubstituents R^(1.3.2) may be identical or different, (c) a heteroarylgroup optionally substituted by 1, 2 or 3 substituents R^(1.3.2) whichis selected from among benzimidazole, benzothiophene, furan, imidazole,indole, isoxazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrrole, thiazole, thiophene and triazole, wherein thesubstituents R^(1.3.2) may be identical or different, (d) a heterocyclicgroup optionally substituted by 1, 2 or 3 substituents R^(1.3.2),wherein the substituents R^(1.3.2) may be identical or different,R^(1.3.1) denotes (a) H, halogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, (b)—O—R^(1.3.1.1), —O—C₁₋₆-alkylene-NR^(1.3.1.2)R^(1.3.1.3),—CO₂R^(1.3.1.1), —C(O)—NR^(1.3.1.2)R^(1.3.1.3),—SO₂—NR^(1.3.1.2)R^(1.3.1.3), —NR^(1.3.1,2)—SO₂—R^(1.3.1.3), —CN,—NR^(1.3.1.2)R^(1.3.1.3), —O—C(O)—R^(1.3.1.1) or (c) a C₁₋₃-alkyl orC₁₋₃-alkyl-O— group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, R^(1.3.2) denotes (a) halogen, C₁₋₆-alkyl,C₃₋₆-cycloalkyl, (b) —O—R^(1.3.2.1), —O—(CH₂)_(s)—O—R^(1.3.2.1),—CO₂R^(1.3.2.1), —S(O)_(m)—R^(1.3.2.2), —CN, —O—C(O)—R^(1.3.2.1) or (c)a C₁₋₃-alkyl group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, R^(1.3.1.1) denotes (a) H, (b) C₁₋₆-alkyl,C₃₋₆-cycloalkyl, aryl, heteroaryl, benzyl which may be substituted by agroup R^(1.3.1.1.1), or (c) a C₁₋₃-alkyl group wherein each methylenegroup is substituted by up to two fluorine atoms and each methyl groupis substituted by up to three fluorine atoms, R^(1.3.1.1.1) denotes HO—or C₁₋₆-alkyl-O—, R^(1.3.1.2) denotes (a) H, (b) C₁₋₃-alkyl, phenyl orbenzyl, wherein the groups may be unsubstituted or substituted byhalogen, HO— or H₃C—O—, R^(1.3.1.3) denotes (a) H, (b) C₁₋₃-alkyl,phenyl or benzyl, wherein the groups may be unsubstituted or substitutedby halogen, HO— or H₃C—O—, or R^(1.3.1.2) and R^(1.3.1.3) together mayalso form a ring which is selected from among azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl and morpholinyl, wherein the ring may beunsubstituted or substituted by a substituent R^(1.3.1.1), R^(1.3.2.1)denotes (a) H, (b) C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, heteroaryl, benzylwhich may be substituted by a group R^(1.3.2.1.1), or (c) a C₁₋₃-alkylgroup wherein each methylene group is substituted by up to two fluorineatoms and each methyl group is substituted by up to three fluorineatoms, R^(1.3.2.1.1) denotes HO— or C₁₋₆-alkyl-O—, R^(1.3.2.2) denotes(a) H, (b) C₁₋₃-alkyl, phenyl or benzyl, wherein the groups may beunsubstituted or substituted by halogen, HO— or H₃C—O—, R^(1.3.2.3)denotes (a) H, (b) C₁₋₃-alkyl, phenyl or benzyl, wherein the groups maybe unsubstituted or substituted by halogen, HO— or H₃C—O—, orR^(1.3.2.2) and R^(1.3.2.3) together may also form a ring which isselected from among azetidinyl, pyrrolidinyl, piperidinyl, piperazinyland morpholinyl, wherein the ring may be unsubstituted or substituted bya substituent R^(1.3.2.1), m denotes one of the numbers 0, 1 or 2, and sdenotes one of the numbers 1, 2 or 3, the tautomers, the diastereomers,the enantiomers, the hydrates, the mixtures thereof and the saltsthereof as well as the hydrates of the salts, particularly thephysiologically acceptable salts thereof with inorganic or organic acidsor bases.
 6. Compounds of general formulae Ia and Ib according to claim1, wherein R², R³, R⁴ and R⁵ are defined as in claim 1 and R¹ denotes agroup selected from

the tautomers, the diastereomers, the enantiomers, the hydrates, themixtures thereof and the salts thereof as well as the hydrates of thesalts, particularly the physiologically acceptable salts thereof withinorganic or organic acids or bases.
 7. Compounds of general formulae Iaand Ib according to claim 1, wherein U, V, X, Y, R¹, R³ and R⁴ aredefined as in claim 1, 2, 3, 4, 5 or 6 and R² denotes a hydrogen atom,the tautomers, the diastereomers, the enantiomers, the hydrates, themixtures thereof and the salts thereof as well as the hydrates of thesalts, particularly the physiologically acceptable salts thereof withinorganic or organic acids or bases.
 8. Compounds of general formulae Iaand Ib according to claim 1, wherein R¹, R² and R⁵ are defined as inclaim 1, 2, 3, 4, 5, 6 or 7 and R³ denotes (a) H, (b) C₁₋₆-alkyl, (c) aC₃₋₆-cycloalkyl group substituted by one or two groups R^(3.2), (d) aC₁₋₃-alkyl group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, R^(3.2) independently of one another denote (a) H, (b)halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, (c) a C₁₋₃-alkyl- or—O—C₁₋₃-alkyl group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, R⁴ denotes (a) H, (b) C₁₋₆-alkylene-R^(4.1), (c) aC₃₋₆-cycloalkyl group substituted by one or two groups R^(4.2), (d) aC₅₋₇-cycloalkenyl group substituted by one or two groups R^(4.2), (e) anaryl group substituted by one or two groups R^(4.2), (f) aC₅₋₇-cycloalkyl group which may be fused to an aryl or heteroaryl group,while the resultant bicyclic group is additionally substituted by one ortwo groups R^(4.2), or (g) a heteroaryl group substituted by one or twogroups R^(4.2), R^(4.1) denotes (a) H, (b) a phenyl group substituted bythe groups R^(4.1.1) and R^(4.1.2), (c) a heteroaryl group substitutedby the groups R^(4.1.1) and R^(4.1.2), R^(4.1.1) denotes (a) H, (c)halogen, C₁₋₃-alkyl, —OH, —CN, —O—C₁₋₃-alkyl, —NR^(4.1.1.1)R^(4.1.1.2),—S—C₁₋₃-alkyl, —NR^(4.1.1.1)—C(O)—C₁₋₃-alkyl,—C(O)—NR^(4.1.1.1)R^(4.1.1.2), —C(O)—O—R^(4.1.1.3), (d) a C₁₋₃-alkyl or—O—C₁₋₃-alkyl group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, R^(4.1.1.1) denotes H, C₁₋₃-alkyl, R^(4.1.1.2) denotesH, C₁₋₃-alkyl, or R^(4.1.1.1) and R^(4.1.1.2) together with the nitrogenatom to which they are bound also denote a group selected frommorpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, pyrrolidinyl andazetidinyl, R^(4.1.1.3) denotes H, C₁₋₃-alkyl, R^(4.1.2) denotes (a) H,(b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, (c) a C₁₋₃-alkyl or—O—C₁₋₃-alkyl group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, or R^(4.2) independently of one another denote (a) H,(b) halogen, C₁₋₃-alkyl, —OH, —CN, —O—C₁₋₃-alkyl, —NR^(4.2.1)R^(4.2.2),—S—C₁₋₃-alkyl, —NR^(4.2.1)—C(O)—C₁₋₃-alkyl, —C(O)—NR^(4.2.1)R^(4.2.2),—C(O)—O—R^(4.2.3), (c) a C₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein eachmethylene group is substituted by up to two fluorine atoms and eachmethyl group is substituted by up to three fluorine atoms, R^(4.2.1)denotes H, C₁₋₃-alkyl and R^(4.2.2) denotes H, C₁₋₃-alkyl, or R^(4.2.1)and R^(4.2.2) together with the nitrogen atom to which they are boundalso denote a group which is selected from among morpholinyl,thiomorpholinyl, piperidinyl, piperidonyl, piperazinyl, pyrrolidinyl andazetidinyl, and which may additionally be substituted by one or twogroups selected from F, —OH, —O—C₁₋₃-alkyl, —OCF₃, C₁₋₃-alkyl and CF₃,R^(4.2.3) denotes H, C₁₋₃-alkyl, R³ and R⁴ together with the nitrogenatom to which they are bound denote: (a) a saturated 5-, 6- or7-membered heterocyclic group which is substituted at a carbon atom by agroup R^(4.3) or by two groups R^(4.3) and R^(4.4), (b) a saturated 5-,6- or 7-membered heterocyclic group which is substituted at two adjacentcarbon atoms by in each case a group R^(4.3) and R^(4.4), (c) asaturated 5-, 6- or 7-membered heterocyclic group which is substitutedat a carbon atom by a group R^(4.3) or by two groups R^(4.3) and R^(4.4)and is additionally fused to a 5-, 6- or 7-membered cycloalkyl orheterocyclyl group, while the fused-on cycloalkyl or heterocyclyl groupis substituted by 1, 2 or 3 groups R^(4.5), (d) a monounsaturated 5-, 6-or 7-membered heterocyclic group which is substituted at a carbon atomby a group R^(4.3) or by two groups R^(4.3) and R^(4.4) and isadditionally fused to a phenyl group, while the fused-on phenyl group issubstituted by 1, 2 or 3 groups R^(4.5), (e) a monounsaturated 5-, 6- or7-membered heterocyclic group which is substituted at a carbon atom by agroup R^(4.3) or by two groups R^(4.3) and R^(4.4) and is additionallyfused to a 5- or 6-membered heteroaryl group, while the fused-onheteroaryl group is substituted by 1, 2 or 3 groups R^(4.5), or (f) aheteroaryl group which is substituted at 1, 2 or 3 carbon atoms by agroup R^(4.5), R^(4.3) denotes H, C₁₋₃-alkyl, phenyl,—C₁₋₃-alkylene-R^(4.3.1), C₁₋₃-alkyl-O—C(O)—, HO—C(O)—, F,—O—C₁₋₃-alkyl, —OH, —CN R^(4.3.1) denotes H, C₁₋₃-alkyl-O—C(O)—, —NH₂,(C₁₋₄-alkyl)-NH—, (C₁₋₄-alkyl)₂N, heterocyclyl, R^(4.4) denotes (a) H,C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl or (b) a C₁₋₃-alkyl- or —O—C₁₋₃-alkylgroup wherein each methylene group is substituted by up to two fluorineatoms and each methyl group is substituted by up to three fluorineatoms, R^(4.3) and R^(4.4) together with the carbon atoms to which theyare bound also denote a C₃₋₆-cycloalkyl, C₅₋₆-cycloalkenyl orheterocyclyl group, R^(4.5) independently of one another denote (a) H,(b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, —NH₂, —CN,—C(O)—O—R^(4.5.1), —C(O)—NR^(4.5.2)R^(4.5.3), (c) a C₁₋₃-alkyl- or—O—C₁₋₃-alkyl group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, (d) phenyl, R^(4.5.1) denotes H, C₁₋₃-alkyl, R^(4.5.2)denotes H, C₁₋₃-alkyl and R^(4.5.3) denotes H, C₁₋₃-alkyl, thetautomers, the diastereomers, the enantiomers, the hydrates, themixtures thereof and the salts thereof as well as the hydrates of thesalts, particularly the physiologically acceptable salts thereof withinorganic or organic acids or bases.
 9. Compounds of general formulae Iaand Ib according to claim 1, wherein R¹, R² and R⁵ are defined as inclaim 1, 2, 3, 4, 5, 6 or 7 and R³ denotes (a) H, (b) C₁₋₆-alkyl, (c) aC₃₋₆-cycloalkyl substituted by one or two groups R^(3.2), or (d) aC₁₋₃-alkyl group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, R^(3.2) independently of one another denote (a) H, (b)halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, (c) a C₁₋₃-alkyl or—O—C₁₋₃-alkyl group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, R⁴ denotes (a) H, (b) C₁₋₆-alkylene-R^(4.1), (c) aC₃₋₆-cycloalkyl group substituted by one or two groups R^(4.2), (d) aC₅₋₇-cycloalkenyl group substituted by one or two groups R^(4.2), (e) anaryl group substituted by one or two groups R^(4.2), (f) aC₅₋₆-cycloalkyl group which may be fused to a phenyl, thiazole orthienyl group, while the resultant bicyclic group is additionallysubstituted by one or two groups R^(4.2), R^(4.1) denotes (a) H, (b) aphenyl group substituted by the groups R^(4.1.1) and R^(4.1.2),R^(4.1.1) denotes (a) H, (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl,—CN, —C(O)—O—R^(4.1.1.3), (c) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl groupwherein each methylene group is substituted by up to two fluorine atomsand each methyl group is substituted by up to three fluorine atoms,R^(4.1.1.3) denotes H, C₁₋₃-alkyl, R^(4.1.2) denotes (a) H, (b) halogen,C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, (c) a C₁₋₃-alkyl or —O—C₁₋₃-alkyl groupwherein each methylene group is substituted by up to two fluorine atomsand each methyl group is substituted by up to three fluorine atoms, orR^(4.2) independently of one another denote (a) H, (b) halogen,C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, —CN, —NH₂, —O—C(O)—C₁₋₃-alkyl, (c) aC₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R³ and R⁴ together with thenitrogen atom to which they are bound denote: (a) a saturated 5- or6-membered heterocyclic group which is substituted at a carbon atom by agroup R^(4.3) or by two groups R^(4.3) and R^(4.4), (b) a saturated 5-or 6-membered heterocyclic group which is substituted at two adjacentcarbon atoms by in each case a group R^(4.3) and R^(4.4), (c) asaturated 5-, 6- or 7-membered heterocyclic group which is substitutedat a carbon atom by a group R^(4.3) or by two groups R^(4.3) and R^(4.4)and is additionally fused to a 5-, 6- or 7-membered cycloalkyl orheterocyclyl group, while the fused-on cycloalkyl or heterocyclyl groupis substituted by 1, 2 or 3 groups R^(4.5), (d) a monounsaturated 5-, 6-or 7-membered heterocyclic group which is substituted at a carbon atomby a group R^(4.3) or by two groups R^(4.3) and R^(4.4) and isadditionally fused to a phenyl group, while the fused-on phenyl group issubstituted by 1, 2 or 3 groups R^(4.5), (e) a monounsaturated 5-, 6- or7-membered heterocyclic group which is substituted at a carbon atom by agroup R^(4.3) or by two groups R^(4.3) and R^(4.4) and is additionallyfused to a 5- or 6-membered heteroaryl group, while the fused-onheteroaryl group is substituted by 1, 2 or 3 groups R^(4.5) and isselected from among

(f) a heteroaryl group which is substituted at 1, 2 or 3 carbon atoms byin each case a group R^(4.5), R^(4.3) denotes H, C₁₋₃-alkyl, phenyl,—C₁₋₃-alkylene-R^(4.3.1), HO—C(O)—, F, —O—C₁₋₃-alkyl, —OH, —CN R^(4.3.1)denotes H, C₁₋₃-alkyl-O—C(O)—, —NH₂, (C₁₋₄-alkyl)-NH—, (C₁₋₄-alkyl)₂N—,morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, azetidinyl,R^(4.4) denotes (a) H, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl or (b) aC₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R^(4.3) and R^(4.4) togetherwith the carbon atoms to which they are bound also denote aC₃₋₆-cycloalkyl or heterocyclyl group, and R^(4.5) independently of oneanother denote (a) H, (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, —NH₂,—CN, (c) a C₁₋₃-alkyl or —O—C₁₋₃-alkyl group wherein each methylenegroup is substituted by up to two fluorine atoms and each methyl groupis substituted by up to three fluorine atoms, or (d) phenyl, thetautomers, the diastereomers, the enantiomers, the hydrates, themixtures thereof and the salts thereof as well as the hydrates of thesalts, particularly the physiologically acceptable salts thereof withinorganic or organic acids or bases.
 10. Compounds of general formulaeIa and Ib according to claim 1, wherein R¹, R² and R⁵ are defined as inclaim 1, 2, 3, 4, 5, 6 or 7 and R³ denotes (a) H, (b) C₁₋₆-alkyl, (c) aC₃₋₆-cycloalkyl group substituted by one or two groups R^(3.2), or (d) aC₁₋₃-alkyl group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, R^(3.2) independently of one another denote (a) H, (b)halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, (c) a C₁₋₃-alkyl- or—O—C₁₋₃-alkyl group wherein each methylene group is substituted by up totwo fluorine atoms and each methyl group is substituted by up to threefluorine atoms, R⁴ denotes (a) H, (b) C₁₋₆-alkylene-R^(4.1), (c) aC₃₋₆-cycloalkyl group substituted by one or two groups R^(4.2), (d) aC₅₋₇-cycloalkenyl group substituted by one or two groups R^(4.2), (e) aphenyl group substituted by one or two groups R^(4.2), (f) aC₅₋₆-cycloalkyl group which may be fused to a phenyl, thiazolyl orthienyl group, while the resultant bicyclic group is additionallysubstituted by one or two groups R^(4.2), R^(4.1) denotes (a) H, (b) aphenyl group substituted by the groups R^(4.1.1) and R^(4.1.2),R^(4.1.1) denotes (a) H, (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl,—CN, —C(O)—O—R^(4.1.1.3), (c) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl groupwherein each methylene group is substituted by up to two fluorine atomsand each methyl group is substituted by up to three fluorine atoms,R^(4.1.1.3) denotes H, C₁₋₃-alkyl, R^(4.1.2) denotes (a) H, (b) halogen,C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, (c) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl groupwherein each methylene group is substituted by up to two fluorine atomsand each methyl group is substituted by up to three fluorine atoms, orR^(4.2) denotes (a) H, (b) halogen, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl, —CN,—NH₂, (c) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylenegroup is substituted by up to two fluorine atoms and each methyl groupis substituted by up to three fluorine atoms, or R³ and R⁴ together withthe nitrogen atom to which they are bound denote: (a) a saturated 5- or6-membered heterocyclic group which is selected from among piperidinyl,piperidinonyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyland pyrrolidinonyl, and which is substituted at a carbon atom by a groupR^(4.3) or by two groups R^(4.3) and R^(4.4), (b) a saturated 5- or6-membered heterocyclic group which is selected from among piperidinyl,piperidinonyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyland pyrrolidinonyl, and which is substituted at two adjacent carbonatoms by in each case a group R^(4.3) and R^(4.4), (c) a saturated 5-,6- or 7-membered heterocyclic group which is selected from amongpiperidinyl, piperidinonyl, morpholinyl, thiomorpholinyl, piperazinyl,pyrrolidinyl, pyrrolidinonyl, azepanyl, diazepanyl, diazepanonyl andoxazepanyl, and which is substituted at a carbon atom by a group R^(4.3)or by two groups R^(4.3) and R^(4.4) and is additionally fused to a 5-,6- or 7-membered cycloalkyl or heterocyclyl group, which is selectedfrom among piperidinyl, piperidinonyl, morpholinyl, thiomorpholinyl,piperazinyl, pyrrolidinyl, pyrrolidinonyl, azepanyl, diazepanyl,diazepanonyl and oxazepanyl, while the fused-on cycloalkyl orheterocyclyl group is substituted by 1, 2 or 3 groups R^(4.5), (d) amonounsaturated 5-, 6- or 7-membered heterocyclic group which isselected from among

and which is substituted at a carbon atom by a group R^(4.3) or by twogroups R^(4.3) and R^(4.4) and is additionally fused to a phenyl group,wherein the fused-on phenyl group is substituted by 1, 2 or 3 groupsR^(4.5), (e) a monounsaturated 5-, 6- or 7-membered heterocyclic groupwhich is selected from among

and which is substituted at a carbon atom by a group R^(4.3) or by twogroups R^(4.3) and R^(4.4) and is additionally fused to a 5- or6-membered heteroaryl group, wherein the fused-on heteroaryl group issubstituted by 1, 2 or 3 groups R^(4.5) and is selected from among

(a) a heteroaryl group which is selected from among indole, isoindole,azaindole, indazole and benzimidazole, and which is substituted at 1, 2or 3 carbon atoms by a group R^(4.5), R^(4.3) denotes H, C₁₋₃-alkyl,phenyl, —C₁₋₃-alkylene-R^(4.3.1), HO—C(O)—, F, —O—C₁₋₃-alkyl, —OH, —CN,R^(4.3.1) denotes H, C₁₋₃-alkyl-O—C(O), —NH₂, (C₁₋₄-alkyl)-NH,(C₁₋₄-alkyl)₂N, morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl,azetidinyl, R^(4.4) denotes (a) H, C₁₋₃-alkyl, —OH, —O—C₁₋₃-alkyl or (b)a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, R^(4.3) and R^(4.4) togetherwith the carbon atoms to which they are bound also denote aC₃₋₆-cycloalkyl group or a heterocyclyl group which is selected fromamong azetidinyl, pyrrolidinyl, piperidinyl and azepanyl, and R^(4.5)independently of one another denote (a) H, (b) halogen, C₁₋₃-alkyl, —OH,—O—C₁₋₃-alkyl, —NH₂, —CN, (c) a C₁₋₃-alkyl- or —O—C₁₋₃-alkyl groupwherein each methylene group is substituted by up to two fluorine atomsand each methyl group is substituted by up to three fluorine atoms, or(d) phenyl, the tautomers, the diastereomers, the enantiomers, thehydrates, the mixtures thereof and the salts thereof as well as thehydrates of the salts, particularly the physiologically acceptable saltsthereof with inorganic or organic acids or bases.
 11. Compounds ofgeneral formulae Ia and Ib according to claim 1, wherein R¹, R² and R⁵are defined as in claims 1, 2, 3, 4, 5, 6 or 7 and R³ denotes (a) H, (b)C₁₋₃-alkyl, (c) a C₁₋₃-alkyl group wherein each methylene group issubstituted by up to two fluorine atoms and each methyl group issubstituted by up to three fluorine atoms, and R⁴ denotes H or a groupselected from

R³ and R⁴ together with the nitrogen atom to which they are bound denotea group selected from

the tautomers, the diastereomers, the enantiomers, the hydrates, themixtures thereof and the salts thereof as well as the hydrates of thesalts, particularly the physiologically acceptable salts thereof withinorganic or organic acids or bases.
 12. Compounds of general formulaeIa and Ib according to claim 1, wherein R¹, R², R³ and R⁴ are defined asin claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 and R⁵ denotes H orC₁₋₃-alkyl, the tautomers, the diastereomers, the enantiomers, thehydrates, the mixtures thereof and the salts thereof as well as thehydrates of the salts, particularly the physiologically acceptable saltsthereof with inorganic or organic acids or bases.
 13. Compounds ofgeneral formulae Ia and Ib according to claim 1, wherein R¹ denotes agroup selected from

R² denotes H, R³ denotes (a) H, (b) C₁₋₃-alkyl, (c) a C₁₋₃-alkyl groupwherein each methylene group is substituted by up to two fluorine atomsand each methyl group is substituted by up to three fluorine atoms, andR⁴ denotes H or a group selected from

R³ and R⁴ together with the nitrogen atom to which they are bound denotea group selected from

R⁵ denotes H or C₁₋₃-alkyl, the tautomers, the diastereomers, theenantiomers, the hydrates, the mixtures thereof and the salts thereof aswell as the hydrates of the salts, particularly the physiologicallyacceptable salts thereof with inorganic or organic acids or bases. 14.The following compounds of general formulae Ia and Ib according to claim1: No. Structure (1)

(2)

(3)

(4)

(5)

(6)

(7)

(8)

(9)

(10)

(11)

(12)

(13)

(14)

(15)

(16)

(17)

the enantiomers, the diastereomers, the hydrates, the mixtures thereofand the salts thereof as well as the hydrates of the salts, particularlythe physiologically acceptable salts thereof with inorganic or organicacids or bases.
 15. Physiologically acceptable salts of the compoundsaccording to one of claims 1 to 14 with inorganic or organic acids orbases.
 16. Pharmaceutical compositions, containing a compound accordingto one of claims 1 to 14 or a physiologically acceptable salt accordingto claim 15 optionally together with one or more inert carriers and/ordiluents.
 17. Use of a compound according to one of claims 1 to 15 forpreparing a medicament for the acute and prophylactic treatment ofheadaches, particularly migraine or cluster headaches and tensionheadaches.
 18. Use of a compound according to one of claims 1 to 15 forpreparing a pharmaceutical composition for the treatment ofnon-insulin-dependent diabetes mellitus (“NIDDM”), cardiovasculardiseases, morphine tolerance, diarrhoea caused by clostridium toxin,skin diseases, particularly thermal and radiation-induced skin damageincluding sunburn, lichen, pruritis, pruritic toxidermies and severeitching, inflammatory diseases, e.g. inflammatory diseases of the joints(osteoarthritis, rheumatoid arthritis, neurogenic arthritis),generalised soft-tissue rheumatism (fibromyalgia), neurogenicinflammation of the oral mucosa, inflammatory lung diseases, allergicrhinitis, asthma, COPD, diseases accompanied by excessive vasodilatationand resultant reduced blood supply to the tissues, e.g. shock andsepsis, chronic pain, e.g. diabetic neuropathies, neuropathies inducedby chemotherapy, HIV-induced neuropathies, postherpetic neuropathies,neuropathies induced by tissue trauma, trigeminal neuralgias,temporomandibular dysfunctions, CRPS (complex regional pain syndrome),back pain, and visceral complaints, such as e.g. irritable bowelsyndrome (IBS), inflammatory bowel syndrome, for relieving pain ingeneral, or for preventive or acute therapeutic treatment of thesymptoms of menopausal hot flushes caused by vasodilatation andincreased blood flow in oestrogen-deficient women and hormone-treatedpatients with prostate carcinoma and castrated men.
 19. Use of acompound according to one of claims 1 to 15 for preparing a medicamentfor the acute and prophylactic treatment of migraine and clusterheadaches, for the treatment of irritable bowel syndrome (IBS) and forthe preventive and acute therapeutic treatment of hot flushes inoestrogen-deficient women.
 20. Method of preparing a medicamentaccording to claim 16, characterised in that a compound according to oneof claims 1 to 15 is incorporated in one or more inert carriers and/ordiluents by a non-chemical method.